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Lecture 18. Terpenes and Cell Signaling, Part 2

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I can't believe it's gone so I can't believe it's gone so quickly said bittersweet quickly said bittersweet high and loved teaching this class high and loved teaching this class it's hard for for me to give his very it's hard for for me to give his very last lecture OK last lecture OK sectarian pick up where we sectarian pick up where we left off last time left off last time small-molecule control over small-molecule control over signaling pathways and we're signaling pathways and we're talked about this last last talked about this last last lecture today proposals you make sure you lecture today proposals you make sure you don't leave the class without getting in if don't leave the class without getting in if you are misleading it you are misleading it and for whatever reason then to and for whatever reason then to spring upon my office is possible spring upon my office is possible you have till Nunes agrees you have till Nunes agrees area and this also applies if area and this also applies if you need to get abstract enter you need to get abstract enter something like that and I like something like that and I like you abstract to the you abstract to the proposal on your proposal on your granddad strategy if you don't granddad strategy if you don't have a great abstract with you today have a great abstract with you today run getting bring it back to you the run getting bring it back to you the media to the TAC media to the TAC critical variant do that critical variant do that SAP there's a little bit of a SAP there's a little bit of a grace period but you know 1 grace period but you know 1 extended to foreign extended to foreign on descended some on descended some issues that turning that company issues that turning that company will have issues that write this will have issues that write this chatty get those over the next chatty get those over the next 24 hours uploaded OK 24 hours uploaded OK sometimes it just stands sometimes it just stands with this kind in the quarters with this kind in the quarters so there's a lot of assignments they're so there's a lot of assignments they're coming and hopefully turn dark coming and hopefully turn dark comedy that together under the comedy that together under the processes of probable that make processes of probable that make arrangements but Fidel and arrangements but Fidel and just keep trying and then just keep trying and then get that forbidden by and 24 get that forbidden by and 24 hours but I do have a quick hours but I do have a quick question for you for next year did question for you for next year did you like having a few today you like having a few today would you rather have a Monday that would you rather have a Monday that underwrote a favorite today underwrote a favorite today research and with the not research and with the not out Monday at the the out Monday at the the upcoming Monday flight the know days now upcoming Monday flight the know days now OK said today on OK OK said today on OK and Monday wow is almost and Monday wow is almost completely evenly completely evenly divided are well my case divided are well my case will probably stick with that is the reason is will probably stick with that is the reason is that gives you more time to read the that gives you more time to read the proposals that it takes a lot of proposals that it takes a lot of time for me to read 120 time for me to read 120 10 page papers and 10 page papers and provide comments on them so and provide comments on them so and because of that I need extra because of that I need extra days and also I feel like you guys days and also I feel like you guys need a little bit of great to study through need a little bit of great to study through the final exams if you had this the final exams if you had this hanging over you you would imagine hanging over you you would imagine just you know working working working just you know working working working until the very last minute of until the very last minute of I'm OK ,comma looking forward to reading I'm OK ,comma looking forward to reading them so you can now relax I them so you can now relax I know you're here and I just know you're here and I just make sure that I get them at the end of make sure that I get them at the end of the court that ended today on this the court that ended today on this table over here a retired you table over here a retired you have office hours today immediately have office hours today immediately after class I imagine that after class I imagine that you don't have to many important you don't have to many important things to talk to me that I will have things to talk to me that I will have opposite hours next quarter If you opposite hours next quarter If you want to stop by under which want to stop by under which always costly Welcome to my always costly Welcome to my office because euro welcomed the start office because euro welcomed the start by usually office hours the best way by usually office hours the best way to get hold of Simeon e-mail to get hold of Simeon e-mail and you know if you need and you know if you need advice about anything advice about anything about careers about about careers about finding a job or whatever I finding a job or whatever I don't hesitate to call on the peso don't hesitate to call on the peso you been my class you work you been my class you work hard for me this quarter all workers for hard for me this quarter all workers for you in the future the it's here so we you in the future the it's here so we talked about on Thursday said talked about on Thursday said Thursday we wrapped up a Thursday we wrapped up a discussion of Turkey's In discussion of Turkey's In and Out then we talked and Out then we talked about cell signaling about cell signaling and 1 thing I want to impress and 1 thing I want to impress upon you is that this upon you is that this concept of using small concept of using small molecules to control molecules to control cells and to cells and to coordinate responses and coordinate responses and sells is really a sells is really a universal phenomenon this universal phenomenon this is carried out by the simple is carried out by the simple organisms on the planet the most organisms on the planet the most complicated organisms is complicated organisms is carried out by humans and stand carried out by humans and stand by humans is done by by humans is done by insects that it is truly insects that it is truly universal it's 1 of those universal it's 1 of those aspects of life that we aspects of life that we find in small molecules find in small molecules are also used extensively are also used extensively by chemical biologist by chemical biologist as power tools for as power tools for dissecting biological dissecting biological phenomena and I showed phenomena and I showed you examples of this you examples of this using both reverse and using both reverse and forward chemical genetics the forward chemical genetics the example of the chemical example of the chemical genetics were those massive genetics were those massive screens to identify screens to identify compounds that could compounds that could interview with my toes that's interview with my toes that's OK we saw this during the OK we saw this during the cell division and that of cell division and that of the DNA instead of lining the DNA instead of lining up on the screen and flying up on the screen and flying neatly in the center was getting neatly in the center was getting was you know pushed to the was you know pushed to the Tabriz and it looks Tabriz and it looks like a complete reversal of what like a complete reversal of what should happen so lower should happen so lower chemical genetics is a chemical genetics is a powerful way to identify powerful way to identify unusual unusual phenotypes in itself phenotypes in itself then using reverse then using reverse chemical genetics you could chemical genetics you could use that small use that small molecule as a powerful molecule as a powerful tools to figure out tools to figure out exactly what's happening that exactly what's happening that I come from a nostril I come from a nostril emerged as a really emerged as a really interesting inhibitor of interesting inhibitor of nieces and using an nieces and using an inhibitor scientists were able to inhibitor scientists were able to the chemical biologist more the chemical biologist more specifically were able to specifically were able to define a particular define a particular Neeson variant that's Neeson variant that's critical to shoving apart critical to shoving apart the chromosomes and pushing them the chromosomes and pushing them into place during on cell into place during on cell division and that's absolutely division and that's absolutely fascinating process and fascinating process and small molecules that offer small molecules that offer temporal controlled many temporal controlled many time control they also time control they also offer localization you offer localization you can go cement particular can go cement particular spot and we haven't talked about how spot and we haven't talked about how they can be used to they can be used to investigate types that would investigate types that would otherwise be lethal to otherwise be lethal to the organism so all of the organism so all of those aspects are what those aspects are what make small molecules such make small molecules such an integral part of chemical an integral part of chemical biology in the modern era biology in the modern era OK now because often use OK now because often use the small molecules kind of the small molecules kind of like toxicology to like toxicology to investigate cell investigate cell phenomenon and we phenomenon and we oftentimes find oftentimes find ourselves investigating cell ourselves investigating cell signaling pathways and signaling pathways and on my message to you there it on my message to you there it is don't panic OK said if is don't panic OK said if you open the issue of you open the issue of sellers something like that sellers something like that and you look at the last and you look at the last couple of pages they always have couple of pages they always have signal transduction signal transduction diagrams and every month diagrams and every month every week or every couple weeks they every week or every couple weeks they investigated different signaling investigated different signaling pathway and these are pathway and these are daunting and the complexity they daunting and the complexity they look like that of the look like that of the Milky Way in terms of the Milky Way in terms of the number of elements the number of elements the present and adjust they present and adjust they look completely not OK but look completely not OK but that the message there is don't that the message there is don't panic and instead of looking panic and instead of looking at such crazy complexity at such crazy complexity we as chemists can simplify we as chemists can simplify things down to 7 things down to 7 major pathways and I major pathways and I contend that if you contend that if you learn these 7 learn these 7 pathways you'll be pathways you'll be equipped them to understand equipped them to understand anything about the matter how anything about the matter how complex it it's all of that complex it it's all of that complexity can be reduced complexity can be reduced down to just 7 down to just 7 elements are 7 different elements are 7 different types and if we learn that 7 types and if we learn that 7 titling the check OK we titling the check OK we looked at the very 1st of the looked at the very 1st of the 7 of which were the 7 of which were the nuclear receptor based nuclear receptor based pathways and we looked at how pathways and we looked at how steroids have potent steroids have potent activity through pointing to the activity through pointing to the nuclear receptors and then we saw nuclear receptors and then we saw that these had 2 different that these had 2 different modes that there were 2 modes of the modes that there were 2 modes of the nuclear receptor pathways nuclear receptor pathways Federer devastation and Homer Federer devastation and Homer dimerization a question it dimerization a question it will let's return to our will let's return to our
allies 7 canonical allies 7 canonical pathways and I'll remind you pathways and I'll remind you again that we looked at the again that we looked at the steroids finding to the steroids finding to the nuclear receptors and the key nuclear receptors and the key element here was the notion that element here was the notion that these nuclear receptors .period these nuclear receptors .period directly to the directly to the steroids and then these steroids and then these are complexes make their are complexes make their way all the way to the nucleus way all the way to the nucleus where DNA turned on were where DNA turned on were turned off and transcription turned off and transcription takes place that's a very takes place that's a very powerful powerful powerful powerful paradigm for affecting paradigm for affecting cell division cell cell division cell growth and I this is growth and I this is why the steroids like why the steroids like testosterone and testosterone and estrogen and have such estrogen and have such potent on cell-based potent on cell-based effects today I want to pick up effects today I want to pick up a discussion and I a discussion and I discuss with you the other discuss with you the other 6 pathways 6 pathways found in the cell In found in the cell In again I'm going to be emphasizing again I'm going to be emphasizing what's common and what what's common and what simple about these pathways simple about these pathways we could get crazy complex we could get crazy complex but it's just not it's not but it's just not it's not pedagogically useful OK pedagogically useful OK softer you kind of the softer you kind of the stripped-down version and stripped-down version and start like you know what your start like you know what your research projects from 1 of these research projects from 1 of these pathways you'll find quickly that pathways you'll find quickly that things get a little more complex but things get a little more complex but not much more complex than are not much more complex than are excellent get started the excellent get started the two-component pathways two-component pathways these are pathways these are pathways in which they won they lighting and in which they won they lighting and appliances that are outside of the appliances that are outside of the cell up here and there cell up here and there and then died rises to and then died rises to receptors tho and by the way receptors tho and by the way just as a quick preview note that just as a quick preview note that many of the upcoming pathways many of the upcoming pathways are going to feature like and that are going to feature like and that Tony even get inside the Tony even get inside the cell obtained like these guys cell obtained like these guys over here so here's a line and over here so here's a line and it's finally here is an unlikely it's finally here is an unlikely and purple binding here another by and purple binding here another by me up here and none of these me up here and none of these legions of getting through the legions of getting through the plasma membrane plasma membrane instead they're going to instead they're going to affect the confirmation affect the confirmation of proteins that are found on the of proteins that are found on the cell surface and that cell surface and that conformational change conformational change will and transducer will and transducer signal from outside the cell signal from outside the cell inside the cell because that's inside the cell because that's going to be a paradigm for today going to be a paradigm for today
are asking me defines 1 are asking me defines 1
moment in the different from and where we moment in the different from and where we
left off OK we talked about quite left off OK we talked about quite
a bit less time than OK here we a bit less time than OK here we
are number 2 and are number 2 and hour 7 but in this hour 7 but in this case I want to talk to you about case I want to talk to you about controlling cell controlling cell differentiation through a differentiation through a class of molecules called class of molecules called cited kinds often known as cited kinds often known as interleukin variously called interleukin variously called interleukin-2 and this is 1 of interleukin-2 and this is 1 of annoying aspects about the annoying aspects about the biology is that they don't have a biology is that they don't have a uniform nomenclature the way we uniform nomenclature the way we can still so the periodic the can still so the periodic the same year as it is and same year as it is and in Russian border on in Russian border on Sudan anywhere in the Sudan anywhere in the world and but balances world and but balances don't have you pack so they have don't have you pack so they have a little bit more difficulties a little bit more difficulties getting a standardized nomenclature in getting a standardized nomenclature in case of be that as it may sound case of be that as it may sound kind so far and important kind so far and important class of molecules for causing class of molecules for causing cells to differentiate cells to differentiate and on the other and on the other differentiation I wanna talk differentiation I wanna talk about today is a about today is a differentiation into differentiation into various blood cells a case various blood cells a case of this includes red blood of this includes red blood cells Eritrea sites cells Eritrea sites and it also includes the and it also includes the cells and the cells cells and the cells which are crucial to the new which are crucial to the new response to responding to the response to responding to the attack but also attack but also includes a number of other different includes a number of other different variants like platelets which we've variants like platelets which we've already seen as being crucial already seen as being crucial to our blood clotting and to our blood clotting and etc. OK so that all of etc. OK so that all of these are signaling lie these are signaling lie against highlighted against highlighted in bold and blue in bold and blue are examples of are examples of cited kinds that all cited kinds that all more or less have more or less have deceived sort of signaling deceived sort of signaling pathway so rather than us pathway so rather than us RIA and let's learn about RIA and let's learn about poor area forget everything I poor area forget everything I told about 4 and talk about how told about 4 and talk about how to next I'm rather than doing that to next I'm rather than doing that I could just tell you about 1 I could just tell you about 1 example and then from that 1 example and then from that 1 example you can figure out example you can figure out everything else OK so let's I everything else OK so let's I right and I'm talking to you right and I'm talking to you about a favorite of ours when we about a favorite of ours when we see before this is a growth see before this is a growth hormone and human growth hormone and human growth hormone causes Accra mentally hormone causes Accra mentally but this is characterized by but this is characterized by abnormal growth beaches abnormal growth beaches
and in the face-to-face and in the face-to-face of with little distorted of with little distorted hands and feet you just hands and feet you just normally size large normally size large hands and feet I mean really hands and feet I mean really abnormal effects and so abnormal effects and so realizing this slide is out of realizing this slide is out of place area I will get back place area I will get back to government let's get back to you to government let's get back to you and let's focus in the and let's focus in the
example I'm going to show you will be example I'm going to show you will be erythropoietin right here erythropoietin right here and again it's and again it's generalisable to a bunch generalisable to a bunch of other molecules OK so of other molecules OK so
this is a very typical mode for this is a very typical mode for these 2 component these 2 component pathways to meeting that they are pathways to meeting that they are going to cause going to cause dimerization on the dimerization on the cell surface and so here's the cell surface and so here's the molecule Eco up here molecule Eco up here erythropoietin erythropoietin erythropoietin erythropoietin stimulates the formation stimulates the formation of red blood vessels of red blood vessels of red blood cells of red blood cells and on the way it works and on the way it works is a Eritrea EPO up here is a Eritrea EPO up here .period rises and EPO .period rises and EPO receptor on the cell service receptor on the cell service and that allows an and that allows an associated Friday's Jack to associated Friday's Jack to Friday's the 2 possible relate Friday's the 2 possible relate to each other place said this is the to each other place said this is the example of the trains example of the trains fossil relations this guy for fossil relations this guy for us for at this hour fast at this us for at this hour fast at this guy and that in turn on guy and that in turn on allows us correlation of allows us correlation of steps by which died arises steps by which died arises and 5 actually gets into the and 5 actually gets into the nucleus and causes nucleus and causes transcription down here now transcription down here now closer look at the past closer look at the past correlation is to the order because correlation is to the order because this is going to be a major mode for this is going to be a major mode for relay of the signal a you relay of the signal a you know like in track and field never know like in track and field never relented at the time kind relented at the time kind of half the time and over here and of half the time and over here and this is a similar type of this is a similar type of phenomenon in this case that the phenomenon in this case that the time is going to be tough time is going to be tough boss correlated amino boss correlated amino acid side chain on the acid side chain on the surface of the protein and that surface of the protein and that cross-correlation amino acid cross-correlation amino acid side chain is going to create side chain is going to create a new service that a new service that allows something that allows something that otherwise would not be allowed to buy otherwise would not be allowed to buy or it could change the or it could change the confirmation of the confirmation of the protein after it's possible protein after it's possible related OK so what that related OK so what that means is that 5 has means is that 5 has won confirmation appear it won confirmation appear it gets lost correlated and gets lost correlated and then it died rises in then it died rises in absence of isolation is absence of isolation is not right is it's a not right is it's a monomeric protein upon monomeric protein upon dimerization it has a dimerization it has a different confirmation 1 that different confirmation 1 that can combined DNA 1 that in turn can combined DNA 1 that in turn on transcription and 1 that on transcription and 1 that he get through the nuclear he get through the nuclear together into the nuclear OK together into the nuclear OK so this is also turned up so this is also turned up Jack pathway because Jack pathway because Japanese and Japanese and sat by or separately the sat by or separately the playing the role in I'm in playing the role in I'm in there's been a cell signaling there's been a cell signaling NOT that's fairly NOT that's fairly direct bears on only direct bears on only a small number of proteins a small number of proteins between signal here and then back between signal here and then back down here in the nucleus of the down here in the nucleus of the examples that are nearly as examples that are nearly as direct this is a good place to direct this is a good place to start the right with zoom in start the right with zoom in
and take a look at exactly what's and take a look at exactly what's happening so here is a happening so here is a regular Powhatan on regular Powhatan on binding to it's rich EPO binding to it's rich EPO receptor on the cell receptor on the cell surface and these are also surface and these are also called Janus-faced called Janus-faced places and because places and because this is the genesis of the this is the genesis of the doorway God you know that also doorway God you know that also has 2 faces to promote has 2 faces to promote faces and looking both faces and looking both ways on the case of the ways on the case of the post up here so given post up here so given Yukos not perfectly Yukos not perfectly symmetrical but symmetrical but protein results in a protein results in a pseudo symmetrical timer pseudo symmetrical timer of the use of EPO of the use of EPO receptors prices that receptors prices that nothing is exactly nothing is exactly symmetric but it's pretty close symmetric but it's pretty close to symmetric appeared again to symmetric appeared again that's the characteristic of these that's the characteristic of these 2 components signaling 2 components signaling pathways now earlier I showed pathways now earlier I showed you that satisfied you that satisfied molecules upon molecules upon dimerization combined with and dimerization combined with and a series of mode of a series of mode of buying DNA where the DNA is buying DNA where the DNA is coming out toward us so coming out toward us so imagine this long you know imagine this long you know the stranded or the stranded or hillocks unit coming hillocks unit coming out us extending way out in out us extending way out in space and you could see that space and you could see that diver is hazard diver is hazard has the DNA kind of Vice has the DNA kind of Vice stretch it's it's stretch it's it's clamped over the DNA clamped over the DNA and it's looking actively for and it's looking actively for correct DNA sequence correct DNA sequence that could then grab onto and that could then grab onto and signal for transfer for signal for transfer for transcription and again the transcription and again the transcriptionist involved the transcriptionist involved the usual players RNA usual players RNA polymerase in other polymerase in other of transcription of transcription factors that jump on and factors that jump on and get involved OK so if all get involved OK so if all
we have to do is right we have to do is right something brings grabbed 2 something brings grabbed 2 things together on the cell things together on the cell surface the we chemists can surface the we chemists can probably do something like that probably do something like that and so on 1 way to do and so on 1 way to do this would be the identifier this would be the identifier molecule that binds molecule that binds to 1 half of the dimer to 1 half of the dimer like this guy over here that like this guy over here that points gyre B and then points gyre B and then simply form supersymmetric simply form supersymmetric timer that it's serious about timer that it's serious about to years 78 and is to years 78 and is not exactly symmetric not exactly symmetric services not seek to services not seek to symmetric unique can flip it symmetric unique can flip it over like that but it doesn't over like that but it doesn't really matter because as long as really matter because as long as you get these guys close enough for you get these guys close enough for the 2 Jack places the the 2 Jack places the parts correlate each other then parts correlate each other then the trend signal transduction the trend signal transduction takes place and then step by its takes place and then step by its fossil related fossil related viruses and then it viruses and then it goes on to transcription goes on to transcription effect so again all we have effect so again all we have to do is identify a to do is identify a binder to 1 1 of these binder to 1 1 of these receptors and then by receptors and then by simply wording that monomer simply wording that monomer into a dilemma that we into a dilemma that we get something it could turn on get something it could turn on and a signal transduction and a signal transduction and anyone have an idea why you and anyone have an idea why you might want to turn on people who are might want to turn on people who are away what what my wife you might away what what my wife you might want to provide referral want to provide referral Powhatan to patients for Powhatan to patients for example what circumstances would example what circumstances would you want of red blood you want of red blood cells being after surgery cells being after surgery yesterday after surgery yesterday after surgery the patient is low and blood the patient is low and blood lost a lot of blood you blood lost a lot of blood you blood all over the place said a all over the place said a review routinely give EPO review routinely give EPO as a way of stimulating as a way of stimulating blood you know blood blood cell blood you know blood blood cell production that blood cell production production that blood cell production and of course this is wildly and of course this is wildly abuse by athletes who abuse by athletes who also a value also a value of Revlon sells for their of Revlon sells for their oxygen-carrying capacity oxygen-carrying capacity and up until recently and up until recently there were no effective test for there were no effective test for erythropoietin abuse under erythropoietin abuse under really good tests really good tests and this is 1 of the reasons and this is 1 of the reasons why you're seeing all these scandals why you're seeing all these scandals come out as athletes come out as athletes are getting caught in fact there was 1 are getting caught in fact there was 1 in the news in the last week where in the news in the last week where athletes said it completed 8 athletes said it completed 8 years ago were caught because the years ago were caught because the samples were still samples were still refrigerated and you can actually refrigerated and you can actually detect the artificial EPO in the detect the artificial EPO in the civil suit from 8 years ago civil suit from 8 years ago and I think that's going to and I think that's going to happen more and more that that would be happen more and more that that would be chemists are going to get better and better chemists are going to get better and better at analyzing samples and at analyzing samples and finding tiny little quantities finding tiny little quantities of unnatural compounds of unnatural compounds and and you know and and and you know and when athletes who are abusing them when athletes who are abusing them and I incur I think this and I incur I think this is of interest because as as a is of interest because as as a sports watcher I want to watch sports watcher I want to watch real athletics not chemical real athletics not chemical products so little and OK products so little and OK so you now know that you can so you now know that you can readily make chemical version readily make chemical version of producing a of producing a strategy like this before so right strategy like this before so right
now another strategy it would be now another strategy it would be a lot Krueger OK so the a lot Krueger OK so the thing about this that's lovely thing about this that's lovely
is that this compound over here is that this compound over here is specific just for is specific just for giant beat him but I'm much giant beat him but I'm much more crude way to do this more crude way to do this would be the simply and would be the simply and former covalent Daimler former covalent Daimler this is a non-covalent time this is a non-covalent time and it hasn't a chance to be and it hasn't a chance to be specific but not much less specific but not much less specific way to do this specific way to do this would be simply add a chemical would be simply add a chemical crosslinking and I'm showing you crosslinking and I'm showing you this because it illustrates a really this because it illustrates a really important reaction 1 that's important reaction 1 that's used quite a bit in chemical used quite a bit in chemical biology biochemistry biology biochemistry let's case in this let's case in this reaction on the year reaction on the year interferon beta receptor interferon beta receptor to and there are going to be to and there are going to be like yeah it's almost like yeah it's almost unavoidable to have life seems on the unavoidable to have life seems on the surface of pretty lysine surface of pretty lysine is this amino acid side is this amino acid side chain that frequently chain that frequently charge typically possibly charge typically possibly charge and it's very charge and it's very soluble I think to the outer soluble I think to the outer surfaces of proteins are surfaces of proteins are almost always studded with almost always studded with lysine residues and so for lysine residues and so for this reason you can this reason you can react to these react to these lysine and means side lysine and means side chains showed here in their chains showed here in their neutral on the state of what neutral on the state of what they activated carboxyl they activated carboxyl a guy so this is like a a guy so this is like a carboxyl 8 except carboxyl 8 except instead of OH here is instead of OH here is a 7 0 minus its a 7 0 minus its carboxyl IT-related products so carboxyl IT-related products so that instead this hasn't that instead this hasn't been hydroxy sets amid been hydroxy sets amid Esther OK and this NHS Esther OK and this NHS ester is a really good we've ester is a really good we've agreed and so what that means agreed and so what that means then is that this could very then is that this could very readily foreman hammered readily foreman hammered bonds and I'll give bonds and I'll give you a a covalent bonds you a a covalent bonds this is completely this is completely analogous to they the basal analogous to they the basal Isiah of Isiah of activated carboxyl activated carboxyl Acosta that we solve all we Acosta that we solve all we talked about in the bond talked about in the bond formation by DCC many formation by DCC many weeks ago OK so 4 weeks ago weeks ago OK so 4 weeks ago or something like that we talked or something like that we talked about how the began bonds we talked about how the began bonds we talked about how you have to activate the about how you have to activate the carboxyl gasses in this carboxyl gasses in this case was starting with something case was starting with something that's on already that's on already activated its NHS ester activated its NHS ester and on what extraordinary doubts and on what extraordinary doubts reactivity Izetta reacts reactivity Izetta reacts specifically with the specifically with the means and not all of means and not all of those elites proves that our those elites proves that our president 55 molar president 55 molar concentration of water right concentration of water right Waters a whole bunch of OH Waters a whole bunch of OH groups and so on this kind groups and so on this kind of chemical specificity of chemical specificity European of specificity European of specificity allows us to pick out the allows us to pick out the use of the functionalities and then use of the functionalities and then it there are 2 armies from it there are 2 armies from neighboring interferon beta neighboring interferon beta receptors on these 2 receptors on these 2 armies can be dragged armies can be dragged together to form a together to form a covalent bonds that where the covalent bonds that where the link together the and again link together the and again and once to covalently and once to covalently cross-linked things you've brought cross-linked things you've brought these guys together and you can these guys together and you can start signaling through the jacks start signaling through the jacks that pathway take now and I that pathway take now and I want to take a moment to show you want to take a moment to show you how this is useful Hollis how this is useful Hollis reactions use of this thing not reactions use of this thing not so useful OK yeah you could do so useful OK yeah you could do this this experiment it will this this experiment it will work but honestly it's work but honestly it's not going to be giving your patience not going to be giving your patience but this compound of the but this compound of the pharmaceutical because will will pharmaceutical because will will react with every other react with every other lysine and finds it has lysine and finds it has 0 specificity it 0 specificity it OK and you know who knows what OK and you know who knows what kind of an allergic reaction the kind of an allergic reaction the petition will come down with you petition will come down with you just got into the habit of much just got into the habit of much better way to do this a much better way to do this a much more a useful aspect of more a useful aspect of this reaction is to use it this reaction is to use it to modify proteins and to modify proteins and
to improve their solubility to improve their solubility so for for example interferon so for for example interferon alpha to this compound alpha to this compound here it's a protein here it's a protein therapeutics and is therapeutics and is typically have delayed meeting typically have delayed meeting there is this polyethylene there is this polyethylene glycol can polyethylene glycol can polyethylene glycol to hear all that glycol to hear all that appended to the fruity appended to the fruity and so on the way this reaction and so on the way this reaction works is the start within works is the start within NHS ester of peg NHS ester of peg case so that this is polyethylene case so that this is polyethylene glycol This is a polymer that you've glycol This is a polymer that you've seen before and maybe none in this seen before and maybe none in this class but certainly in some organic class but certainly in some organic chemistry and on because chemistry and on because it has activated carboxyl it has activated carboxyl later it will come along and later it will come along and modify all these lights modify all these lights scenes and even these his city scenes and even these his city residents and what's residents and what's remarkable about this is if you remarkable about this is if you control the pH control the pH and the proper conditions and the proper conditions you could set this up so that there you could set this up so that there is only 1 is only 1 position in this complicated position in this complicated protein that actually gets protein that actually gets modified and when we look modified and when we look closely at this what we find closely at this what we find is not a license and is not a license and Pete 6 . 5 again Pete 6 . 5 again modified at pH 6 . modified at pH 6 . 5 all the sightings of 5 all the sightings of protonated and again in the protonated and again in the protonated if the size of protonated if the size of
protonated there's no way they can protonated there's no way they can react with the activated react with the activated carboxyl oxalate instead carboxyl oxalate instead at the 6 . 5 only thing at the 6 . 5 only thing
that's available to react that's available to react and is 1 of the history I and is 1 of the history I believe it's the slide and so the pay believe it's the slide and so the pay gets upended its gets upended its conjugated conjugated specifically just to 1 of specifically just to 1 of histidines everywhere and histidines everywhere and nowhere else in this nowhere else in this complicated duty and naturally complicated duty and naturally exquisite reactivity and exquisite reactivity and selectively and separate selectively and separate reason this is used very reason this is used very extensively in and out of extensively in and out of these kinds of things these kinds of things are used are used extensively in Therapeutics extensively in Therapeutics a pretty Therapeutics a case why a pretty Therapeutics a case why would you want to do this why would you would you want to do this why would you anyone put head on anyone put head on on your approaches Bloomberg on your approaches Bloomberg question but commander b he seem to be question but commander b he seem to be thinking about something you yes will thinking about something you yes will turn around and say so would be turn around and say so would be suggested is that suggested is that this page over here is going this page over here is going to be highly water-soluble to be highly water-soluble right it's going to have a lot right it's going to have a lot of hydrogen bond of hydrogen bond acceptors and so you could take acceptors and so you could take a protein that would be a protein that would be relatively insoluble relatively insoluble and make it more soluble in and make it more soluble in addition to your increasing its addition to your increasing its molecular weight and over molecular weight and over here can be really it can be here can be really it can be hundreds to thousands and hundreds to thousands and so you can take a relatively so you can take a relatively small proteins that would get small proteins that would get excreted very readily by excreted very readily by the kiddies increases the kiddies increases molecular weight and then it gets molecular weight and then it gets recycled back and prevent recycled back and prevent it from being excreted so there's some it from being excreted so there's some huge advantages to huge advantages to solubility soluble as solubility soluble as Asian and other even Asian and other even doing things like decreasing doing things like decreasing the proteins indigenous to the the proteins indigenous to the present decreasing how the hell present decreasing how the hell of a recognized it is of a recognized it is by the new system as being a by the new system as being a foreign invader it all is a foreign invader it all is a really important properties and so really important properties and so this reaction is used very this reaction is used very extensively Katie questions extensively Katie questions about this right now is that the each about this right now is that the each PLC over here indicates PLC over here indicates that you're getting 1 in only that you're getting 1 in only 1 protein out if 1 protein out if there was that this is getting headlight there was that this is getting headlight and a whole bunch of places you would see and a whole bunch of places you would see lots of lots of peaks in case of lots of lots of peaks in case of predominantly cares number predominantly cares number 2 and these guys are relatively 2 and these guys are relatively small area on the move on I small area on the move on I
want talk to next about growth want talk to next about growth hormone and growth Norman hormone and growth Norman pathways and earlier I showed you pathways and earlier I showed you this idea of Accra medley which this idea of Accra medley which is too much growth hormone is too much growth hormone leading to gigantic so that you know leading to gigantic so that you know excessively large can be excessively large can be and touching so this is and touching so this is our 3rd example of a signaling our 3rd example of a signaling pathway and this is pathway and this is a classic This is a classic This is used extensively by used extensively by many different signaling many different signaling legends including legends including TGF-beta here and TGF-beta here and in general this is a very in general this is a very common very typical This is common very typical This is this the beginning and general all this the beginning and general all of these work by the same of these work by the same mechanism the mechanism mechanism the mechanism is dying arise the is dying arise the receptors up here and then receptors up here and then auto parts for a late meeting auto parts for a late meeting this kind a several-year boss this kind a several-year boss correlates the 1 next to correlates the 1 next to it and at this guy passed for life it and at this guy passed for life annexed to this and that annexed to this and that leads to some sort of and leads to some sort of and that allows a kind is that allows a kind is to pass late nearby other to pass late nearby other protein that that goes on protein that that goes on and eventually get down to the DNA and eventually get down to the DNA down here OK but the important down here OK but the important thing is diarization that thing is diarization that auto parts correlation and auto parts correlation and we're just going to see that again and we're just going to see that again and again and again OK so here for again and again OK so here for example is factor receptor example is factor receptor appearance outside as it was appearance outside as it was a great factor receptor in a great factor receptor in purple and these are also purple and these are also called receptor tyrosine called receptor tyrosine places because they're places because they're acting as a tiny since acting as a tiny since the boss tyrosine on each the boss tyrosine on each other and then you end up with a whole other and then you end up with a whole series of different from series of different from that a tire you have a that a tire you have a whole series of different boss whole series of different boss correlated piracy missing correlated piracy missing basically becomes loaded up basically becomes loaded up with all these 4 Oriole terrorist with all these 4 Oriole terrorist note everyone still with me on the cell note everyone still with me on the cell surface stuff done rise on possible surface stuff done rise on possible Pasquale here's a gets complicated Pasquale here's a gets complicated and once you get the and once you get the dimerization and a possible dimerization and a possible relation a total of war relation a total of war pathways have been pathways have been activated this thing goes activated this thing goes on and for example on and for example it on engages the it on engages the stats pathway that we saw stats pathway that we saw earlier when we talked about the earlier when we talked about the 2 components signaling 2 components signaling pathways it also gets into pathways it also gets into the matter tiny some pathway the matter tiny some pathway which all described next year but which all described next year but also starts to affect the also starts to affect the P-I 3 Chinese PLC P-I 3 Chinese PLC gamma tap weights as well the use gamma tap weights as well the use of pathways associated with of pathways associated with fatty acids which we fatty acids which we briefly alluded to earlier the briefly alluded to earlier the last later on Thursday of last later on Thursday of last week when we looked at fatty last week when we looked at fatty acid synthesis acid synthesis and signaling in and signaling in itself and I'm initially itself and I'm initially albeit the pick up and show you albeit the pick up and show you exactly what's going on when we exactly what's going on when we talk about that kind of signaling talk about that kind of signaling want before we do let's take a want before we do let's take a closer look at this protein closer look at this protein at the top is a growth factor at the top is a growth factor
human growth for format for human growth for format for growth factors it's unlikely growth factors it's unlikely and edited Diana rise the and edited Diana rise the receptor tyrosine Chinese receptor tyrosine Chinese RTK at the RTK at the self-service and 100 self-service and 100 is we've already seen this protein is we've already seen this protein is the familiar pretty to us this is the familiar pretty to us this is human growth hormone over is human growth hormone over here and it's going to here and it's going to initiate this ionization initiate this ionization through having to binding through having to binding sites and earlier this sites and earlier this quarter we talked about fact quarter we talked about fact this is 1 of the very earliest this is 1 of the very earliest lectures might have been like the 3rd lectures might have been like the 3rd week of something we talked about week of something we talked about 1 of these binding 1 of these binding sites and how it had a sites and how it had a hotspot of binding energy for hotspot of binding energy for binding to receptor binding to receptor tyrosine Chinese human growth tyrosine Chinese human growth hormone binding protein on the hormone binding protein on the cell's surface there is a cell's surface there is a 2nd binding site 2nd binding site that's that looks completely that's that looks completely different and this was on the other different and this was on the other side that allows the side that allows the dimerization of the dimerization of the receptor tyrosine is to take receptor tyrosine is to take place cases as a model for place cases as a model for satellite interactions which is satellite interactions which is widely seen it before them but you widely seen it before them but you don't necessarily have to don't necessarily have to have a large proteins have a large proteins doing this diarization impact doing this diarization impact small molecules that can be small molecules that can be very potent at doing that very potent at doing that
and so for example this PD and so for example this PD compound over here 1 compound over here 1 has great specificity for has great specificity for for particular growth for particular growth factor receptors on the factor receptors on the cell surface and on these cell surface and on these numbers over here I see numbers over here I see fifties animal and recall fifties animal and recall that smaller number that smaller number indicates higher potency indicates higher potency right because that means a right because that means a lower-key which means greater lower-key which means greater affinity and noticed that these affinity and noticed that these compounds are selected for compounds are selected for the action that yes the the action that yes the fetal growth factor fetal growth factor receptors that you receptors that you are 1 2 and 3 are 1 2 and 3 verses that yes this is verses that yes this is a vascular a vascular endothelial growth factor endothelial growth factor receptor which stimulates receptor which stimulates KGO Genesis the growth of KGO Genesis the growth of blood vessels that we talked about blood vessels that we talked about earlier we talked about earlier we talked about and the producers and the and the producers and the finding a needle OK so this finding a needle OK so this sort of specificity for sort of specificity for 1 class of these receptors 1 class of these receptors over other receptors in the over other receptors in the same class is prized same class is prized and medicinal chemists will and medicinal chemists will spend a lot of time trying to spend a lot of time trying to optimize the structure of optimize the structure of a compound like this 1 such a compound like this 1 such that it will be specific for that it will be specific for 1 of these receptors or 1 of these receptors or maybe for all classes these maybe for all classes these receptors but then avoid receptors but then avoid saying each year far saying each year far endothelial growth factor endothelial growth factor receptor board you know something like receptor board you know something like stock which is really broad stock which is really broad that brought activity became what that brought activity became what this means then is that you can have this means then is that you can have ways of targeting ways of targeting tumors selectively and tumors selectively and what we're showing here are 2 were what we're showing here are 2 were treated our tumors treated our tumors dissected out of an animal that had dissected out of an animal that had been treated with the compound been treated with the compound on the left versus on the left versus controls and checking how much controls and checking how much smaller the size of a peso that's smaller the size of a peso that's a good sign and so on if we have a good sign and so on if we have ways of targeting ways of targeting blocking inhibiting the growth blocking inhibiting the growth factor receptors we have factor receptors we have really put it into cancer really put it into cancer compounds and this is 1 of the compounds and this is 1 of the frontiers of Iran frontiers of Iran medicinal chemistry chemical medicinal chemistry chemical biology of many Indians biology of many Indians get their specificity through get their specificity through binding not to the liking binding not to the liking and finding side that was and finding side that was highlighted by the slide highlighted by the slide
it over here with the login it over here with the login like supplied rather they like supplied rather they seem to prefer to bind seem to prefer to bind
to the ATP binding site to the ATP binding site and actually seems to be a and actually seems to be a surprising area for surprising area for cleaning specificity you cleaning specificity you you wouldn't expect that's right because you'd you wouldn't expect that's right because you'd expect every kind of case that expect every kind of case that uses a all kinds of his uses a all kinds of his ATP that's the source of ATP that's the source of phosphate but you wanted and phosphate but you wanted and expect them all to find expect them all to find ATP in the same sort of way ATP in the same sort of way but what we're finding out through but what we're finding out through efforts of medicinal chemistry efforts of medicinal chemistry is that actually and there's enough is that actually and there's enough variation in the ATP variation in the ATP binding site that you binding site that you can you can alter the can you can alter the structures of these structures of these compounds and compounds and specificity say F G specificity say F G F R versus all of these F R versus all of these other receptors down here so other receptors down here so by what I mean by this by by what I mean by this by bearing structural complied ,comma bearing structural complied ,comma during the structure would be for during the structure would be for example on changing the example on changing the structure of history of structure of history of functionality I'm showing you this functionality I'm showing you this is the you urea you might is the you urea you might wanna GI of dental urea wanna GI of dental urea you might want to try and I know a straight you might want to try and I know a straight guy Udall the RIA etc. to guy Udall the RIA etc. to imagine making lots and lots imagine making lots and lots of little changes over here of little changes over here over here over here and over here over here and doing this to dial-in doing this to dial-in the specificity but for the specificity but for particular receptor this is particular receptor this is a property it's also known as a property it's also known as selective and it makes sense selective and it makes sense I would stake a closer look I would stake a closer look than a possible relations than a possible relations
possible relation is not just possible relation is not just a random so these guys you on a random so these guys you on a possible relating to each other a possible relating to each other and you pension duty or something but and you pension duty or something but I'm going to do it in a very I'm going to do it in a very seek a very seek a very specific sequence of specific sequence of blows in other words and blows in other words and they're going to have a very they're going to have a very defined pathway of defined pathway of 1 possible relation 1 possible relation allows the next possible relation allows the next possible relation with blouse and exports for with blouse and exports for relations and that illustrated by relations and that illustrated by these numbers every year which these numbers every year which detail and this guy gets detail and this guy gets lost related 1st this lost related 1st this skydiver 2 2nd 3 4 and skydiver 2 2nd 3 4 and 5 and so on and so 5 and so on and so forth and so the longer forth and so the longer this diver hangs this diver hangs around the more likely around the more likely it is actually allows it is actually allows signaling into those various signaling into those various pathways and remember this for pathways and remember this for pathways that are going to be pathways that are going to be implicated by this 1 implicated by this 1 receptor appear pay so the receptor appear pay so the receptor tyrosine case receptor tyrosine case goes to town but it doesn't goes to town but it doesn't start gone wild and start gone wild and randomly instead is very randomly instead is very specific and in that specific and in that specificity it's going to be specificity it's going to be turning on specific turning on specific pathways let's take a look at pathways let's take a look at
this at 1 of these pathways as this at 1 of these pathways as the Mac kind pathway this is the Mac kind pathway this is 1 of the 4 at the protein is that 1 of the 4 at the protein is that a single thrilled and so a single thrilled and so after after the spot after after the spot correlation takes place a correlation takes place a protein within S H 2 protein within S H 2 tutoring culture 1 can tutoring culture 1 can grab onto this grab onto this prostate and then on prostate and then on get past correlated itself get past correlated itself allowing GM to divine allowing GM to divine rather too also has a rather too also has a message to main H 2 message to main H 2 domains following to possible domains following to possible related tyrosine in fact related tyrosine in fact I think we saw them earlier in the I think we saw them earlier in the quarter but rather too quarter but rather too as a as a polypropylene helix that can polypropylene helix that can be bound by an S be bound by an S H 3 domains H 3 domains allowing binding to roust allowing binding to roust allowing mining to round and allowing mining to round and then in and met then in and met earlier work which then gets earlier work which then gets into the into the nucleus of an into the into the nucleus of an earlier I told you how there earlier I told you how there was alternative nomenclature so was alternative nomenclature so matters there is a lot can matters there is a lot can also be called not trainees also be called not trainees countries and then in part for countries and then in part for relates snack Heidi's I've even relates snack Heidi's I've even seen that trainees trainees trainees seen that trainees trainees trainees so there's a bunch of other places so there's a bunch of other places in this pathway that I'm sort of in this pathway that I'm sort of not showing you and I not showing you and I and also simplifying the and also simplifying the nomenclature I'm using the simplest nomenclature I'm using the simplest nomenclature as well OK the nomenclature as well OK the important part here is that important part here is that there's kind of a hand off a there's kind of a hand off a signal that involves not just fast signal that involves not just fast correlation but interaction correlation but interaction through message to me and we've seen through message to me and we've seen that earlier in the quarter earlier that earlier in the quarter earlier
in the quarter I showed you how in the quarter I showed you how polypropylene polypropylene sequences will buying sequences will buying into S H 3 domains into S H 3 domains in fact here's structure that I in fact here's structure that I showed you hear an S H Street showed you hear an S H Street a main ingredient here is the a main ingredient here is the polypropylene it's a new member polypropylene it's a new member This is the Helix This is the This is the Helix This is the 310 likes but if you look 310 likes but if you look down this access see looks down this access see looks triangular looks triangular triangular looks triangular here this is what the here this is what the polypropylene looks like so polypropylene looks like so this is a familiar concept to this is a familiar concept to us this is something that we see us this is something that we see before we've also seen H 2 before we've also seen H 2 domains as well OK so domains as well OK so
drab too as a drab too as a message to to bind to the pastor message to to bind to the pastor tyrosine unchecked 1 but tyrosine unchecked 1 but also has a message 3 also has a message 3 that points to senate that points to senate Federalist soft Over here Federalist soft Over here
OK and it's also once OK and it's also once arrested once for the service arrested once for the service with me right is 1 of the with me right is 1 of the elements that this pathway elements that this pathway illustrates that also illustrates that also prototypical this is 1 of those prototypical this is 1 of those things that you see quite often on things that you see quite often on the cell surface that on cell the cell surface that on cell surfaces not unit of surfaces not unit of sterile the we did you sterile the we did you environment rather the cell environment rather the cell surface is complicated it surface is complicated it has a lot of shrubbery has a lot of shrubbery on it and in fact on on it and in fact on amongst the shrubbery is amongst the shrubbery is long chains of this stuff called long chains of this stuff called heparin sulfate this can heparin sulfate this can then attract FDI then attract FDI figures track the lighting and figures track the lighting and that these growth factor receptors that these growth factor receptors like and decrease the like and decrease the enhanced their apparent enhanced their apparent affinity for pointing to the affinity for pointing to the receptor simply by proximity receptor simply by proximity effect case of the shrubbery up effect case of the shrubbery up here the heparin sulfate here the heparin sulfate grabs onto any stuff grabs onto any stuff that happens the passing by and that happens the passing by and then because now it's then because now it's localized up close to localized up close to the receptor the receptors and the receptor the receptors and then more likely find more then more likely find more easily find and that in easily find and that in turn enhances signaling turn enhances signaling ability take some that's so these ability take some that's so these are common notes and we're are common notes and we're seeing all the common mode seeing all the common mode that I want to learn a society that I want to learn a society that heparin is out here to that heparin is out here to enhance finding enhance finding dimerization takes place on dimerization takes place on a possible relations takes place a possible relations takes place there is binding through S there is binding through S H 2 and S H 3 H 2 and S H 3 domains and then a relay domains and then a relay of possible relations of possible relations consolation and then consolation and then finally into the nucleus for finally into the nucleus for transcription Hi psyche the transcription Hi psyche the various said baseball it's just various said baseball it's just running throwing catching running throwing catching and eating what the more complicated and eating what the more complicated than that cases a few elements than that cases a few elements here but organist use it would you here but organist use it would you get into this area using the get into this area using the same elements repeated over same elements repeated over and over again learn these and over again learn these elements will be able to elements will be able to understand everything else the understand everything else the questions so far we got on let's questions so far we got on let's
talk a little bit about the other talk a little bit about the other pathways that these pathways that these receptor tyrosine kind receptor tyrosine kind like to and stimulate and like to and stimulate and 1 of these another pathway 1 of these another pathway bars on these pathways bars on these pathways that are on our that are on our own fatty acid and own fatty acid and signaling pathways and signaling pathways and these include of the possible these include of the possible inositol 3 kind inositol 3 kind is this is fossil is this is fossil inositol 3 and inositol 3 and there are kind there are kind cases that pass for later so cases that pass for later so 3 K was the lives of all 3 3 K was the lives of all 3 tiny for those caught the eye 3 tiny for those caught the eye 3 came up costs for relates the came up costs for relates the 3rd hydroxy of this 3rd hydroxy of this quite clear that so this disliked quite clear that so this disliked and is appended to a fatty and is appended to a fatty acid chain and upon acid chain and upon possible relation this possible relation this gives you on something akin gives you on something akin to a different structure right now to a different structure right now have something that has to be have something that has to be passed secrets attached to passed secrets attached to this like him and on this this like him and on this Senate can allow binding Senate can allow binding this is called a powerful this is called a powerful enough that all 3 here at 3 PM 3 enough that all 3 here at 3 PM 3 and then be bound and and then be bound and by the use by the use of the by the use by the use of the 3 binding sites had the 3 binding sites had the effect here so this is a effect here so this is a protein called protein tiny protein called protein tiny seat or PKC seat or PKC PAC is floating around the PAC is floating around the cell carriers happy is that cell carriers happy is that these you know it's into these you know it's into flowers looking for that whatever this flowers looking for that whatever this does all that OK until it does all that OK until it finds pit 3 once it finds pit 3 once it finds the 3 it gets finds the 3 it gets ensnared like fish getting ensnared like fish getting stuck onto a bishop at stuck onto a bishop at that point PKC is that point PKC is done at the cell membrane done at the cell membrane and this localizes and this localizes PKC at the cell PKC at the cell membrane work and start membrane work and start doing all kinds of things doing all kinds of things peso again and this is the peso again and this is the principle of localization principle of localization and globalization is and globalization is what allows these things what allows these things then get turned on and then then get turned on and then it turns out that the pathways it turns out that the pathways kind like that all that into real kind like that all that into real estate location location estate location location location pay and so in the location pay and so in the same way that have friends same way that have friends is confining these lie is confining these lie against a particular spots in the against a particular spots in the self this step 3 is going self this step 3 is going to confine PKC to confine PKC just particular spots at the just particular spots at the plasma membrane and that in plasma membrane and that in turn is going to allow the turn is going to allow the halfway to get kicked off a place halfway to get kicked off a place that's not simply activity that's not simply activity it's also looking it's also looking localization localization localization localization localization that gets localization that gets things into the right spot things into the right spot where they can do the most signaling where they can do the most signaling it makes sense to pay this is a it makes sense to pay this is a grossly simplified portrait grossly simplified portrait when you start looking at this in more when you start looking at this in more detail once you start finding that detail once you start finding that there are other ways of sharing sort there are other ways of sharing sort so for example you can free so for example you can free up the like him from the up the like him from the rest of the on the easel rest of the on the easel detail by by a detail by by a hydrolase he'll gamble hydrolase he'll gamble over here and things get more over here and things get more complicated as well OK In complicated as well OK In
addition to the heparin addition to the heparin sulfate that ever told you about sulfate that ever told you about there is also and the there is also and the various IP 3 various IP 3 seasons victories there's also seasons victories there's also curious role played by curious role played by calcium and the release of calcium and the release of calcium so I P 3 the calcium so I P 3 the release of the IP release of the IP 3 from the pit 3 1 3 from the pit 3 1 has the effect of releasing has the effect of releasing calcium into the cell and this calcium into the cell and this in turn under hinges in turn under hinges a binding a binding site to allow blinding this site to allow blinding this stuff down here at the plasma stuff down here at the plasma membrane OK so all this membrane OK so all this stuff is working together a case stuff is working together a case so you have on a really so you have on a really complicated dance complicated dance where on 1 of the major where on 1 of the major gold so the dancers simply to gold so the dancers simply to get the players into the right get the players into the right space at the right time OK space at the right time OK and I'm calcium is great and I'm calcium is great because it diffuses very readily because it diffuses very readily through the cell and it works really through the cell and it works really well for this questions well for this questions about the receptor tyrosine about the receptor tyrosine kindnesses growth hormone kindnesses growth hormone etc Hi this is 90 per etc Hi this is 90 per cent of cell signaling really cent of cell signaling really is what I just told you thank I'm is what I just told you thank I'm not going to go on and I'll talk to you not going to go on and I'll talk to you about other outside I don't need to about other outside I don't need to say 90 per cent 30 per say 90 per cent 30 per cent 40 per cent of cent 40 per cent of cell signaling that you read cell signaling that you read about in science teacher about in science teacher itself the UN is close itself the UN is close deals with these pathways I would deals with these pathways I would talk to you have another 30 per cent talk to you have another 30 per cent so this is a really important 1 so this is a really important 1
g protein coupled g protein coupled receptors are some of the most receptors are some of the most common proteins in the human common proteins in the human body on these really are body on these really are extremely abundant to us extremely abundant to us humans and that these are the humans and that these are the proteins that make life worth proteins that make life worth living these are the things that allow living these are the things that allow us to see and like us to see and like rhodopsins over here allow us to rhodopsins over here allow us to smell like these factory smell like these factory things allows the taste things allows the taste and here's some tasty ones and here's some tasty ones and etc. all of and etc. all of these bonds smell these bonds smell molecules taste molecules taste molecules work by molecules work by binding to G protein binding to G protein coupled receptors which look coupled receptors which look like that this is a like that this is a trans membrane proteins trans membrane proteins were the membrane is going were the membrane is going through here thanks to through here thanks to membrane that cuts through membrane that cuts through this over here and there this over here and there on the wagon is very on the wagon is very deeply buried it gets deeply buried it gets snuggle down deep into snuggle down deep into this GPC PCR and this GPC PCR and inside the GPC inside the GPC art exchanges the art exchanges the confirmation GPC confirmation GPC are such that the stuff in are such that the stuff in here that's going to be signaling here that's going to be signaling on the inside in the on the inside in the cytoplasm of the protein cytoplasm of the protein has a new confirmation said has a new confirmation said these find you a very wide these find you a very wide range alike and that many of range alike and that many of these are promiscuous and these are promiscuous and activity meaning all point to activity meaning all point to a bunch of tasty things on a bunch of tasty things on the and once that happens the and once that happens that allows the that allows the conformational change that conformational change that communicates from what's communicates from what's happening outside the cell to the happening outside the cell to the inside of the cell types so inside of the cell types so that's kind of at the very cell that's kind of at the very cell surface let's take a closer surface let's take a closer look at a height I have to tell you look at a height I have to tell you
a little bit about how these a little bit about how these work and I 1st want to work and I 1st want to tell you and what about dynamic tell you and what about dynamic range of summer digress range of summer digress for a moment and then we're going to take a for a moment and then we're going to take a closer look at a case so that closer look at a case so that if for example you have some if for example you have some receptor that I'm receptor that I'm simply was turned on simply was turned on and off depending on if you and off depending on if you have a finding by like and you have a finding by like and you have a kind of a lousy have a kind of a lousy sensor OK so these sensor OK so these have active sensors have active sensors located on a deal to say since located on a deal to say since like changing the new a like changing the new a unit moving towards toward unit moving towards toward flight after some organisms flight after some organisms or you know being able to or you know being able to smell so that it determines smell so that it determines whether or not you eat this whether or not you eat this food that's going to kill you or not food that's going to kill you or not kill make it possible for you to live on kill make it possible for you to live on there's any credible there's any credible premium on being of premium on being of sense title quantities sense title quantities and at the same time the of the and at the same time the of the sense from the quantity of pay and sense from the quantity of pay and that's that's a property called that's that's a property called dynamic range if the dynamic range if the sensor simply sensor simply operates on the principle operates on the principle of bound or of bound or unbound your dynamic unbound your dynamic range is going to be very range is going to be very limited OK and let me limited OK and let me remind you that this remind you that this principle of bound versus principle of bound versus unbound is governed by an unbound is governed by an on and operates that on and operates that together have a dissociation together have a dissociation constant associated with that constant associated with that and the truth is this offers a and the truth is this offers a limited dynamic range as limited dynamic range as epitomized by on this epitomized by on this this 1 cent activity this 1 cent activity plot that we showed earlier plot that we showed earlier in the class work all these in the class work all these habits avoid all what had habits avoid all what had this avoid all type of this avoid all type of relationship between relationship between concentration alike and an concentration alike and an activity on the Y activity on the Y axis that the problem with this axis that the problem with this is that from this type of is that from this type of receptor would be sensitive receptor would be sensitive only in these 3 or 4 only in these 3 or 4 orders of magnitude in orders of magnitude in concentrations from 10 concentrations from 10 to the minus 7 to 10 to the to the minus 7 to 10 to the minus 4 peso like some minus 4 peso like some
milling Moeller to some micro milling Moeller to some micro Moeller and that might be OK Moeller and that might be OK but it's not so OK if you but it's not so OK if you have the smell an oak tree have the smell an oak tree quantities of some quantities of some experiment to know whether or not experiment to know whether or not that you know you're ever going to find me in that you know you're ever going to find me in your lifetime OK that's the your lifetime OK that's the kind of important if you're an kind of important if you're an organism right and so on this organism right and so on this business about 5 cents business about 5 cents
a only in 1 particular a only in 1 particular range is pretty much range is pretty much worthless paper or really worthless paper or really good sensing and devising good sensing and devising really good senses so really good senses so instead all of which he instead all of which he PCR is relying on PCR is relying on a different principle if I get a different principle if I get a different principle does anyone have a different principle does anyone have questions about this 1 does make questions about this 1 does make sense to you that this is kind of sense to you that this is kind of limited in its utility limited in its utility I always get nervous when there's I always get nervous when there's the questions take your word for it the questions take your word for it but instead to keep you but instead to keep you
could be achieved protein could be achieved protein coupled receptors coupled receptors signal through a G signal through a G protein they all going protein they all going directly to something called the G directly to something called the G protein and the G protein and the G protein is a catalyst protein is a catalyst that catalyze that catalyze hydrolysis of hydrolysis of GTP this guy GTP this guy appear magnesium appear magnesium GDP complex to GDP complex to magnesium GDP so magnesium GDP so it's simply high of bosses it's simply high of bosses hydrolysis of hydrolysis of Indiana prostate of Indiana prostate of GDP to give us GDP GDP to give us GDP a straightforward reaction a a straightforward reaction a reaction we've seen before the reaction we've seen before the easy 1 right it easier easy 1 right it easier actually within Ridenour actually within Ridenour sleeping drawn mechanism a sleeping drawn mechanism a slate of here's important part slate of here's important part by coupling binding to by coupling binding to the activity of an the activity of an enzyme you can very enzyme you can very sensitively to the on sensitively to the on the activity and the activity and too this sense of pesos too this sense of pesos becomes a really exquisite becomes a really exquisite sensor for low concentrations in sensor for low concentrations in high concentrations and I high concentrations and I realize it's not clear at this moment realize it's not clear at this moment amateur you before I do go amateur you before I do go around with me on this idea around with me on this idea GPC are pointed you GPC are pointed you proteins G proteins are proteins G proteins are catalysts remove that went OK catalysts remove that went OK so check this out here's what's so check this out here's what's really going on OK so really going on OK so on gene protein in on gene protein in its GDP its GDP downstate but says downstate but says signal off pays GPC signal off pays GPC yards up here if the G yards up here if the G protein however is found protein however is found duty-paid signal gets shut duty-paid signal gets shut off on the other hand it's off on the other hand it's bound to GTT this bound to GTT this signal gets turned on a pay signal gets turned on a pay and what's important is that and what's important is that there are 2 there are 2 intermediary of intermediary of enzymes that are gonna enzymes that are gonna catalyze and help catalyze and help push this equilibrium between push this equilibrium between GDP down and GDP down and GTP about these 2 GTP about these 2 Our of guanine Our of guanine nucleotide exchange factor nucleotide exchange factor again that that helps again that that helps push out GDP To allow push out GDP To allow binding by and then in the binding by and then in the opposite direction a opposite direction a GPA's activating GPA's activating protein forget that helps protein forget that helps us the boss correlation of us the boss correlation of GDP the GDP OK GDP the GDP OK here the way this works here the way this works yourselves think yourselves think carefully control the carefully control the Riccio of death to Riccio of death to staff were gathered together and by staff were gathered together and by doing that they could make doing that they could make this signal the on sensor more this signal the on sensor more sensitive 1 less sensitive 1 less sensitive painted you want to sensitive painted you want to be more sensitive be more sensitive and you basically set it and you basically set it up so it's always signal up so it's always signal or rates and you have a or rates and you have a lot gaps around the lot gaps around the gaps keep in this gaps keep in this offstage so if anything offstage so if anything turns it on over here in the turns it on over here in the room everything goes on on the other room everything goes on on the other hand if you want to be less hand if you want to be less sensitive to keep it in the sensitive to keep it in the signal on state so they signal on state so they really takes quite a bit to get really takes quite a bit to get a shot off again makes sense a shot off again makes sense this is a really powerful this is a really powerful principal man and on it's principal man and on it's 1 that I really have not seen 1 that I really have not seen in too many areas in too many areas of electronics for the of electronics for the chemistry and it's 1 that I think really chemistry and it's 1 that I think really could be exploited for an interesting could be exploited for an interesting use the there is also the only use the there is also the only 1 per cent of all things OK so 1 per cent of all things OK so you mean have had as this happened you mean have had as this happened on actually he's always is there on actually he's always is there is only 1 such as little is only 1 such as little water although there was water although there was 355 more water but the 355 more water but the GDP over here GDP over here bound by that time the G bound by that time the G protein it is getting protein it is getting hospitalized at a very slow hospitalized at a very slow rates the catalyst here is rates the catalyst here is not such a great catalyst and not such a great catalyst and GDP in Water is GDP in Water is completely stable it's not going to completely stable it's not going to get idolizing needs an get idolizing needs an enzyme Titleist on the enzyme Titleist on the time scale that's relevant for time scale that's relevant for biology look at and question here biology look at and question here said OK so this is happening right said OK so this is happening right up close to the heart the plasma up close to the heart the plasma membrane right up close to the membrane right up close to the self-service cases GVC self-service cases GVC hours right there at the cell service the hours right there at the cell service the G protein is right below G protein is right below grabbing on holding on for dear grabbing on holding on for dear life and then these life and then these guessing gaps heartwarming guessing gaps heartwarming and another piece of the and another piece of the sandwich soon and get the sandwich soon and get the monster complexes again monster complexes again over here instead investing over here instead investing yes I'd like to see them In a letter to you yes I'd like to see them In a letter to you if you would get the same if you would get the same dynamic range of 10 so if dynamic range of 10 so if you just the concentration you just the concentration alike down here you're only alike down here you're only going over quarters the going over quarters the magnitude of dynamic range magnitude of dynamic range appeared that he had this gap and appeared that he had this gap and them then you can tune in to them then you can tune in to make the Spanish of this over make the Spanish of this over said now response the said now response the widely and over here were widely and over here were widened over here this is you widened over here this is you responsiveness over all responsiveness over all of these this dynamic of these this dynamic range OK and this is what you need to range OK and this is what you need to know that the money explained the know that the money explained the face of this is the same this is face of this is the same this is the same set of receptors the same set of receptors that's going to allow you to see and that's going to allow you to see and you know there's times when you need to be you know there's times when you need to be of the sea and dark caves of the sea and dark caves to be able to survive the nite to be able to survive the nite you but it's certainly your primeval you but it's certainly your primeval ancestors right they would ancestors right they would need to build a surviving dark need to build a surviving dark caves where humans sense caves where humans sense 1 photon OK we 1 photon OK we can sense just a few can sense just a few photons that kind of low-light photons that kind of low-light sensitivity incredibly sensitivity incredibly important on the other hand important on the other hand eventually you get out of the eventually you get out of the cave and your wandering cave and your wandering around in the bright sunlight and of around in the bright sunlight and of all you can see our unity could all you can see our unity could see each photon individually you're see each photon individually you're going to get totally overwhelmed going to get totally overwhelmed and you're not you'll see and you're not you'll see anything right so you need a anything right so you need a system that allows you to system that allows you to build a sense things way down build a sense things way down here but then also here but then also appealed to shut off so appealed to shut off so that it doesn't get overwhelmed way that it doesn't get overwhelmed way up here OK and that's really the up here OK and that's really the key to this activity so far key to this activity so far affecting the Gap and Gap affecting the Gap and Gap ratio controls that that ratio controls that that sensitivity OK question No sensitivity OK question No
that's also part of it as well that's also part of it as well OK but you know the road oxen OK but you know the road oxen sensing about times that has sensing about times that has to have some way of Irish of of the to have some way of Irish of of the less sensitive times more less sensitive times more sensitive front but certainly yes sensitive front but certainly yes you're right dilation of the you're right dilation of the peoples and will have an peoples and will have an effect as well and over here the watch effect as well and over here the watch OK but if you modify the wide OK but if you modify the wide again and and make a more again and and make a more sensitive than others say sensitive than others say you're you're viewing you're you're viewing tastes or something you make it more tastes or something you make it more sweet right but sweet right but eventually you know you're here's eventually you know you're here's your daddy like hammering on its your daddy like hammering on its
about wines really well over about wines really well over here eventually Sistani get here eventually Sistani get overwhelmed gets saturated overwhelmed gets saturated rated so area really hastily rated so area really hastily that's not so pleasant OK so that's not so pleasant OK so
what happens after the g what happens after the g protein so were up here we protein so were up here we have a binding to the g have a binding to the g protein coupled receptors protein coupled receptors and here are the key key and here are the key key proteins these have 3 proteins these have 3 subunits and help other people subunits and help other people subunit found out what it subunit found out what it is that the helpless going to be is that the helpless going to be doing it activity that I talked doing it activity that I talked about this is not going to about this is not going to lead to ventilate lead to ventilate cyclists this protein cyclists this protein over here which turns over the over here which turns over the give cyclic AMP what's give cyclic AMP what's neat about this is that all neat about this is that all of these g protein couple of these g protein couple receptors converge on the receptors converge on the Savannah light cyclists Savannah light cyclists also overdue strong but there also overdue strong but there largely going to converge over here largely going to converge over here and get a lakeside place and get a lakeside place acts as an integrator of acts as an integrator of signals such as you can get signals such as you can get signals from a couple of signals from a couple of different cell surface different cell surface receptors turning on a receptors turning on a cite players which in turn the cite players which in turn the psychology and he turns on psychology and he turns on protein kind stay protein protein kind stay protein trainees ABC before trainees ABC before we talked about this we talked about this protein this is the protein that protein this is the protein that does the waltz as it does the waltz as it passed for relates different passed for relates different proteins in the cell we looked proteins in the cell we looked at at a single molecule at at a single molecule level earlier in this class level earlier in this class and I it's a good and I it's a good friend of everyone is thinking have friend of everyone is thinking have 128 PKA 128 PKA allows credit this allows credit this transcription factor to turn transcription factor to turn on genes for example want to on genes for example want to turn on genes had to do turn on genes had to do something about party at my something about party at my side had proposed purchase side had proposed purchase so it turns out that the so it turns out that the molecules that bind to molecules that bind to the CPC artists are the CPC artists are extremely diverse and in fact extremely diverse and in fact and we humans have have learned to and we humans have have learned to revel in its chemical revel in its chemical diversity so for example the use diversity so for example the use of molecules of molecules associated with the smell of associated with the smell of peanuts you know that nice rose peanuts you know that nice rose the smell of peanuts it's the smell of peanuts it's actually it's not 1 actually it's not 1 molecule rather it's molecule rather it's a plethora of a little place ,comma a plethora of a little place ,comma a library of these a library of these molecules over here that are molecules over here that are present president these different present president these different concentrations that have different concentrations that have different odor thresholds and different odor thresholds and different odor activity values odor activity values and said the odor and said the odor receptors which are cheaper receptors which are cheaper to coupled receptors are going to to coupled receptors are going to find each of these find each of these and then and in turn and then and in turn these are going to matter to these are going to matter to specific neurons OK so specific neurons OK so lots lots different compounds lots lots different compounds each 1 of their and each 1 of their and characteristics now but that sort of characteristics now but that sort of symphony that we associate symphony that we associate of the Rose the smell of peanuts of the Rose the smell of peanuts is a bunch of these present at is a bunch of these present at different concentrations so we different concentrations so we need receptors and need receptors and response to the of different response to the of different molecules and do it in a way molecules and do it in a way that integrates the signal and that integrates the signal and gives us something that reminds us gives us something that reminds us of roasted peanuts here is the of roasted peanuts here is the latest works on the use of the latest works on the use of the
cell receptors that cell receptors that olfactory receptors in the olfactory receptors in the nose gear is over and over here nose gear is over and over here ordering combined to ordering combined to several different several different receptors In the years of receptors In the years of tradition buying weekly this tradition buying weekly this strongly this guy but not strongly this guy but not all this guy and maybe at this all this guy and maybe at this time of year all of these time of year all of these olfactory cells that olfactory cells that have this receptor on the have this receptor on the surface all y all surface all y all signal back through the signal back through the ceiling North case so we ceiling North case so we not that there was set the sells not that there was set the sells over here in this old over here in this old factories and they're all going factories and they're all going to go back to to 1 in to go back to to 1 in only 1 hour on all the ones only 1 hour on all the ones that have the purple GPC that have the purple GPC on the surface all the ones on the surface all the ones that have a the green GCR go that have a the green GCR go back to a different neurons back to a different neurons Islamist punishing result Islamist punishing result that came up was discovered last that came up was discovered last 2 decades or so but in short 2 decades or so but in short what this means is that what this means is that everything that finds this everything that finds this receptor signals in the same receptor signals in the same way you get the same neurons way you get the same neurons firing and I'm in it firing and I'm in it and using that I've and using that I've got to get free share that I got to get free share that I discussed with you this can discussed with you this can allow signaling that tells allow signaling that tells you that the vendor and see whether you that the vendor and see whether or not we have a strong-minded or not we have a strong-minded per week finders so over here per week finders so over here you have a strong minor yet more you have a strong minor yet more signal out over here you have a signal out over here you have a weaker Binder C of a weaker weaker Binder C of a weaker signal coming back out and signal coming back out and again you can control the again you can control the dynamic range stated you dynamic range stated you don't get totally overwhelmed don't get totally overwhelmed if you go into peanut factory if you go into peanut factory so that you know the selling peanuts so that you know the selling peanuts for the next week or something like that for the next week or something like that they are at the talk about vision they are at the talk about vision
I talk you mentioned earlier and I talk you mentioned earlier and this is 1 of those amazing this is 1 of those amazing chemical reactions that all chemical reactions that all of us are reliant upon that of us are reliant upon that we humans especially we humans especially especially reliant upon especially reliant upon vision as their primary vision as their primary sensory organs and I'm with sensory organs and I'm with workable of this is workable of this is on you that goal here is on you that goal here is to capture a photo ID your to capture a photo ID your expectation is you can bind expectation is you can bind to a photo right have you had to a photo right have you had capture of time so instead the capture of time so instead the GPC are GPC are associated vision called associated vision called rhodopsins reduction rhodopsins reduction over here covalently over here covalently links to cope after links to cope after called ready now OK so this is called ready now OK so this is a structure ready now it forms a a structure ready now it forms a shift based with the last shift based with the last seen in the GPC or seen in the GPC or and this is normally and this is normally found in a found in a cesspool of war OK said cesspool of war OK said this 1112 this 1112 carbon-carbon double bonds 6 carbon-carbon double bonds 6 upon being a radiated by upon being a radiated by photons that speech did photons that speech did the CIS all of them and I the CIS all of them and I saw rises to give its saw rises to give its reasons all of them and the net reasons all of them and the net effect here is the weapon of effect here is the weapon of the red and now it's go from the red and now it's go from system to transfer system to transfer and that whole cycle and that whole cycle hexane has slipped from being hexane has slipped from being over here to being now over here to being now extended that has the extended that has the effect of changing the effect of changing the confirmation of the confirmation of the GPC are allowing GPC are allowing you to see this is how you were you to see this is how you were seeing me right there this is how seeing me right there this is how it really works taken now and in it really works taken now and in recent years has started to recent years has started to get creative and we've been get creative and we've been devising rationales that are devising rationales that are responsive to different responsive to different wavelengths and some of these might wavelengths and some of these might be really interesting for allowing us be really interesting for allowing us to see at different to see at different wavelengths for example to build wavelengths for example to build the sea in the infrared the sea in the infrared to see in the dark and so to see in the dark and so on and so forth you can imagine a lot on and so forth you can imagine a lot of interest in this by people like of interest in this by people like to see whether let's take a closer to see whether let's take a closer
look at the structure look at the structure rhodopsins so again it's a rhodopsins so again it's a TPC our notice that its TPC our notice that its structural it's very similar to the structural it's very similar to the GPC or a shot on the 1st GPC or a shot on the 1st line of the CPC line of the CPC hours have a common structural hours have a common structural motifs consisting of motifs consisting of 7 Alpert helices 7 Alpert helices that circumvent the membrane that circumvent the membrane the trans membrane here the trans membrane here in purple is the red in purple is the red again forming a shift based at again forming a shift based at 1 end to a lysine residue 1 end to a lysine residue on this topic likes and on this topic likes and of the protein undergoes a of the protein undergoes a dramatic confirmation dramatic confirmation change in response to change in response to that system inside that system inside summarization since Prince summarization since Prince isomerization is huge isomerization is huge up here this little change appear up here this little change appear at the time and slashing and over at the time and slashing and over here that you get summarization here that you get summarization and filmed the whole protein and filmed the whole protein changes conformation changes conformation changes affecting its finding changes affecting its finding to the G protein and to the G protein and turned signaling through turned signaling through that 1 g protein that 1 g protein cascade that we talked about cascade that we talked about earlier intermediate earlier intermediate stimulation of neurons which stimulation of neurons which again is what you're doing when you again is what you're doing when you see can this kind of extraordinary see can this kind of extraordinary array and any questions about array and any questions about
GBC arts moving on the GBC arts moving on the
yeah so it's constantly yeah so it's constantly flipping back and forth between flipping back and forth between system trams and that's what system trams and that's what you're interpreting its vision you're interpreting its vision carried on financing carried on financing
alliances number 5 an hour alliances number 5 an hour of in our discussion so these of in our discussion so these areas are going the wrong way but areas are going the wrong way but sodium is currently being sodium is currently being pumped out of the cell calcium is pumped out of the cell calcium is being conducted trolled being conducted trolled carefully chloride is being pumped carefully chloride is being pumped in and out of the cell potassium is in and out of the cell potassium is costly because tennis is costly because tennis is cell maintains an cell maintains an equilibrium of equilibrium of specific specific concentrations of its concentrations of its violence those on Ireland's violence those on Ireland's provides a way of provides a way of signaling very quickly in the signaling very quickly in the cell in fact most of the cells cell in fact most of the cells fastest responses fastest responses and such as vision and stuff like and such as vision and stuff like that are probably going through that are probably going through channels OK so the way this channels OK so the way this works is Udinese on works is Udinese on ion channels can open up ion channels can open up corridors that allow ions corridors that allow ions to flow again and this leads to to flow again and this leads to an electrical signal that can an electrical signal that can propagate along in propagate along in neurons for example case so neurons for example case so it's carefully controlled through it's carefully controlled through transporters and provides transporters and provides really fast response said this is really fast response said this is the kind of response where the kind of response where I I knew by suddenly make I I knew by suddenly make a lot of players then you jump or a lot of players then you jump or something like that that's the I'm something like that that's the I'm response you fearing that response you fearing that financial response financial response seeing have fonts OK so seeing have fonts OK so
here's what these channels look here's what these channels look like this it is calcium like this it is calcium activated potassium channel activated potassium channel that allows the have the flow that allows the have the flow and calcium binds down and calcium binds down here changes the confirmation here changes the confirmation and then allows cetaceans to and then allows cetaceans to flow out of the cell and you can flow out of the cell and you can imagine that because these imagine that because these channels allow really channels allow really fast response such as a fast response such as a muscle response and muscle response and toxins would Woodberry toxins would Woodberry potently target these types potently target these types of channels and Kariba of channels and Kariba toxin is about 1 toxin is about 1 in a large numbers of in a large numbers of different toxins that different toxins that target the sites channels target the sites channels many these toxins cause many these toxins cause paralysis these are things that are paralysis these are things that are used by on used by on scorpions and Cobra scorpions and Cobra has etc and that's all I has etc and that's all I have to say about Ryan channels the have to say about Ryan channels the fascinating and am slowly fascinating and am slowly and they flow out I want to move on and they flow out I want to move on
death receptors and so death receptors and so this is a class of this is a class of compounds that binds the compounds that binds the self-service and instead of self-service and instead of causing dimerization causing dimerization because primary station because primary station as you get this active trying as you get this active trying were in fact dimerization were in fact dimerization is associated with shutting all is associated with shutting all the pathway and so for example the pathway and so for example this content over here this content over here and allows encourages the and allows encourages the formation of an inactive formation of an inactive diary that shuts off the diary that shuts off the parkway but getting a little ahead of parkway but getting a little ahead of myself here's what it looks like myself here's what it looks like
why again is up here and why why again is up here and why he ended the trial upon he ended the trial upon binding the receptor forms binding the receptor forms a triangle and then you get a a triangle and then you get a series of races series of races I have to get a series of I have to get a series of Chinese is passing up possible Chinese is passing up possible related response and then in related response and then in an hour and a half of the gets into the an hour and a half of the gets into the cell and causes cell and causes transcription and transcription and information this is a highly information this is a highly regulated process that regulated process that used extensively in the used extensively in the insist this includes things insist this includes things like tea after this like tea after this includes interfere on includes interfere on etc. These are really etc. These are really important pathways for important pathways for turning on information turning turning on information turning on the immune system OK on the immune system OK last pathway number last pathway number 7 and that usable 7 and that usable gas molecules it turns gas molecules it turns out that we humans are out that we humans are susceptible to signaling by susceptible to signaling by the little gas molecules the little gas molecules things like oxygen and things like oxygen and fact on all life is going fact on all life is going to be very dependent upon to be very dependent upon being able % being able % oxygen you can imagine oxygen you can imagine that if he cannot sense that if he cannot sense low-oxygen conditions you're low-oxygen conditions you're gonna die right because you need to be able gonna die right because you need to be able to learn to move storage to learn to move storage areas can brief right that areas can brief right that instinctive breed when you're instinctive breed when you're underwater is fundamental to underwater is fundamental to the life and it's really fundamental the life and it's really fundamental to all organisms that depend to all organisms that depend on oxygen and so the way this on oxygen and so the way this works as oxygen sensing works as oxygen sensing by the sale of works by by by the sale of works by by taking advantage of the taking advantage of the chemical properties of chemical properties of oxygen as an oxygen as an oxygen so there is a oxygen so there is a concentration of hit 1 out concentration of hit 1 out there in in the cell this hit 1 there in in the cell this hit 1 out Wisconsin leaving out Wisconsin leaving synthesizing consciously synthesizing consciously being degraded and on being degraded and on this hit 1 out upon this hit 1 out upon encountering oxygen encountering oxygen oxidises gets oxidises gets oxidized introducing oxidized introducing OH group that in OH group that in turn allows it to be turn allows it to be degraded and that in turn degraded and that in turn will will prevent these will will prevent these transcription pathways from transcription pathways from taking place case so when hit 1 taking place case so when hit 1 out was president of nuclear out was president of nuclear these this causes these this causes transcription which in turn transcription which in turn causes turns on causes turns on anaerobic respiration rate anaerobic respiration rate tell that tells the cell we don't tell that tells the cell we don't have a lot of oxygen present we have a lot of oxygen present we better take into gear the better take into gear the anaerobic respiration anaerobic respiration aspects of our aspects of our metabolism on the other hand of metabolism on the other hand of oxygen is present that oxygen is present that oxidation introduces a oxidation introduces a hydroxyl and that in hydroxyl and that in turn means to turn means to degradation of hit 1 out so degradation of hit 1 out so the key concept here is the key concept here is that we have this that we have this concentration hit 1 out but concentration hit 1 out but that's translating Hong Kong that's translating Hong Kong sleeping integrated and that gives sleeping integrated and that gives you a very rapid sense you a very rapid sense of how much of oxygen is of how much of oxygen is present it's kind of like this that present it's kind of like this that 1 out but it and it's like 1 out but it and it's like thermostat for oxygen thermostat for oxygen levels it's consciously levels it's consciously monitoring how much oxygen was monitoring how much oxygen was also adopted the sell also adopted the sell them apart the oxygen them apart the oxygen it's going to die if it doesn't switch it's going to die if it doesn't switch on these anaerobic on these anaerobic respiration pathways magic respiration pathways magic oxide is also another oxide is also another
very common cell very common cell signaling molecule and signaling molecule and this 1 works by winding to this 1 works by winding to iron ore Franco iron ore Franco factors of 1 elite factors of 1 elite cycling and in turn cycling and in turn causing blood vessels to causing blood vessels to relax so this is important for relax so this is important for the regulation of blood the regulation of blood pressure and so on there a pressure and so on there a number of compounds were number of compounds were invented to Of that this invented to Of that this pathway and it was pathway and it was astonishing is actually worth astonishing is actually worth misses compounds like Viagra were misses compounds like Viagra were found to be less effective found to be less effective as blood pressure as blood pressure regulators and more regulators and more interesting for the side interesting for the side effects the and during their effects the and during their
structures over here these structures over here these are structures Alice are structures Alice and Viagra compounds in the and Viagra compounds in the little blue pill here's the way this little blue pill here's the way this works OK so this is Night works OK so this is Night Magic oxide over here it's Magic oxide over here it's going to bind to a 1 lead going to bind to a 1 lead sideways and in turn sideways and in turn that's going to that GDP that's going to that GDP being converted to being converted to cyclic GMP these cyclic GMP these compounds inhibit Guan compounds inhibit Guan elite sideways and in elite sideways and in turn that causes blood turn that causes blood vessel relaxation and vessel relaxation and this is 1 but this is this is 1 but this is 1 pathway that's very 1 pathway that's very dependent upon calcium dependent upon calcium concentration etc. so concentration etc. so sorry at the site of the sorry at the site of the compounds are gonna be targeting compounds are gonna be targeting key by this compound over here key by this compound over here which is affected by cyclic which is affected by cyclic GMP love OK any GMP love OK any questions about any of the questions about any of the 7 signal transduction 7 signal transduction pathways 2 yeah it's in that pathways 2 yeah it's in that case that brings us to my case that brings us to my wrapped up an exclusion wrapped up an exclusion of what I've been talking to quarter of what I've been talking to quarter
this is a new way of thinking about this is a new way of thinking about biology thinking about it at the biology thinking about it at the level of Adams bonds level of Adams bonds where are we can actually where are we can actually make changes could think created make changes could think created Bill creatively and I hope for Bill creatively and I hope for example the proposal Simon example the proposal Simon has shown you know what it's like to be has shown you know what it's like to be at the frontiers of this really at the frontiers of this really exciting field so these exciting field so these processes that you've probably processes that you've probably seen in other classes seen in other classes innocently idea I innocently idea I DNA the steering etc. DNA the steering etc. but I hope by thinking about but I hope by thinking about these in terms of chemicals in these in terms of chemicals in terms of the new compounds that terms of the new compounds that Adams the bonds and we've Adams the bonds and we've introduced into your thinking of about introduced into your thinking of about new ways of thinking about the new ways of thinking about the reactivity for example reactivity for example forming links deep forming links deep urination etc. Chemical urination etc. Chemical
Biology lets us Biology lets us certain dress who are it certain dress who are it really gets us to it's a really really gets us to it's a really big questions in big questions in biology and all the biology and all the structures that I'm showing up structures that I'm showing up here on things that we've seen this here on things that we've seen this quarter either on quarter either on discussed in lecture or whether discussed in lecture or whether they're in the text of these they're in the text of these include things like that ,comma include things like that ,comma toxin that targets toxin that targets financial and causes financial and causes paralysis and the the other paralysis and the the other organisms on the planet and organisms on the planet and we've seen lots lots of their we've seen lots lots of their and while activities in this and while activities in this class it also lets us class it also lets us
address and where we come from address and where we come from rival we talked about provides rival we talked about provides that the says it was very that the says it was very abstract Ribery using abstract Ribery using it as an example of Europe it as an example of Europe pushing but Chemical Biology pushing but Chemical Biology gives us a gives us a foundation to start foundation to start address really philosophical address really philosophical questions things that humans questions things that humans have been grappling with for a very long have been grappling with for a very long time and finally we get to time and finally we get to dress them really at the level of dress them really at the level of Adams of bonds and then Adams of bonds and then
chemical biology gives us that chemical biology gives us that control of our destiny he control of our destiny he gives us the tools that we gives us the tools that we need to devise need to devise compounds that allow us compounds that allow us to overcome our being to overcome our being human that allow us to address human that allow us to address things like disease things like disease starvation nutritional starvation nutritional deficit etc. and we've been deficit etc. and we've been talking about this all quarters talking about this all quarters here for example is the peg here for example is the peg in introns molecule that I in introns molecule that I showed earlier in in today's showed earlier in in today's lecture this is the head of this big lecture this is the head of this big walked next to it and that's walked next to it and that's the protein that I showed earlier the protein that I showed earlier and he's a really and he's a really important molecules these are important molecules these are molecules that affect the world molecules that affect the world and that allow us to and that allow us to address diseases and address diseases and
I am in any chemical I am in any chemical biology into changing biology into changing society the compounds we society the compounds we talk about have a big talk about have a big impact on our lives they impact on our lives they have an impact that goes beyond have an impact that goes beyond just the medical health they have just the medical health they have impacts on for example impacts on for example affecting athletes for affecting athletes for example have so I would encourage you example have so I would encourage you
to join us join us at the to join us join us at the frontier of chemical biology and frontier of chemical biology and I hope to see you in I hope to see you in laboratories you reduce your laboratories you reduce your mind and I'm really mind and I'm really looking forward to reading your proposals so I looking forward to reading your proposals so I want to thank not only for being want to thank not only for being our projectionist for doing all our projectionist for doing all of the and I have to thank of the and I have to thank of critical appearance in of critical appearance in Merion down here for being really Merion down here for being really outstanding I would affect all of outstanding I would affect all of you for really fun quarter I'd really you for really fun quarter I'd really enjoy teaching you and if you're joining us enjoy teaching you and if you're joining us and you too and I hope to you and you too and I hope to you Susan Collins from you on the Susan Collins from you on the class and when you do it as class and when you do it as well but I really enjoyed teaching this well but I really enjoyed teaching this class and said that you really class and said that you really recorder exploded recorder exploded
Glättung <Oberflächenbehandlung>
Biosynthese
Chemische Reaktion
Pegelstand
Feuer
Muskelrelaxans
Actinium
GMP
Guaninnucleotid-Austauschfaktoren
Zelldifferenzierung
Chemische Bindung
Sulfate
Guaninnucleotid-Austauschfaktoren
Hexane
Interleukin 17
Signalkette
Kalium
Sildenafil
Homocystein
Fülle <Speise>
Elektron <Legierung>
Valenzisomer
Geruchsschwellenwert
Etomidat
Epoxidharz
RNS-Synthese
Raffination
Chemische Reaktion
Bukett <Wein>
Körpergewicht
Biogenese
Interkristalline Korrosion
Kaliumkanal
Weibliche Tote
Zelldifferenzierung
Schussverletzung
Adrenerger Rezeptor
Gap junction
Hydroxybuttersäure <gamma->
Chloride
Tumor
Nährstoff
Agonist
Zellkern
Druckausgleich
Elektrolytische Dissoziation
Bathygraphie
Reaktionsgleichung
Werkzeugstahl
Stockfisch
Reduktionsmittel
Vascular endothelial Growth Factor
Somatotropin
Atombindung
Molvolumen
Aerob-anaerobe Schwelle
Elektronentransfer
Homöopathie
Alpha-2-Rezeptor
Weibliche Tote
Tandem-Reaktion
Aktives Zentrum
Stofftransport <Biologie>
Primärelement
Wasserstand
Phosphorylierung
Polymorphismus
Setzen <Verfahrenstechnik>
Gangart <Erzlagerstätte>
Porphyrin
Mutationszüchtung
Lochfraßkorrosion
Krankheit
Helix <beta->
Blei-208
Verzerrung
Stimulation
CHARGE-Assoziation
Vernetzung <Chemie>
Derivatisierung
Sauerstoffverbindungen
Polypropylen
Initiator <Chemie>
Kernrezeptor
Sauerstoffverbindungen
Stereoselektivität
Kunststoff
Koordinationszahl
Propagation <Chemie>
Wasser
Hydrophobe Wechselwirkung
G-Protein gekoppelte Rezeptoren
Magnesium
Sildenafil
Domäne <Biochemie>
Ionenkanal
Plasmamembran
Membranproteine
Laichgewässer
Verhungern
Sense
Reaktionsmechanismus
Säure
Amine <primär->
Chromosom
Gletscherzunge
Molekül
Lactitol
Beta-Faltblatt
Carboxylierung
Krankengeschichte
Sonnenschutzmittel
Jukos
Zelle
Molekulardynamik
Reaktionsführung
Meeresspiegel
Krebs <Medizin>
Monomere
Amine <primär->
Sterblichkeit
Durchfluss
Topizität
Gesundheitsstörung
Rhodopsin
Gen
Base
Retinal
RNS
Hydrolyse
Thermoformen
Phosphate
Retinoide
Feuer
Abschrecken
Zellteilung
Stimulans
Hydrolyse
Aktivität <Konzentration>
Bioverfügbarkeit
ISO-Komplex-Heilweise
Atombindung
Grenzfläche
Acetylcholinchlorid
Kernrezeptor
Wasserlöslichkeit
RNS-Synthese
Enzym
Orlistat
Guanin
Besprechung/Interview
Sonnenschutzmittel
Inosite
Oxidans
Transkriptionsfaktor
Fluoralkene
Regulatorgen
Klinisches Experiment
Tiermodell
Phosphate
Polymere
Glykolsäure
Stammzelle
Duftstoff
Chemische Struktur
Ionenkanal
Heparin
Sekundärstruktur
Gezeitenstrom
Inhibitor
Seitenkette
Dimere
Plasmamembran
Systemische Therapie <Pharmakologie>
Erythrozyt
Membranproteine
Biologisches Lebensmittel
Aktivität <Konzentration>
Tank
Natrium
Fluoralkene
Toxin
Erdrutsch
Satelliten-DNS
Deformationsverhalten
Sekret
Ader <Geologie>
Chemische Eigenschaft
GTP-bindende Proteine
Konformation
Chromosomenaberration
Ligand
Oberflächenchemie
Heparin
Kettenlänge <Makromolekül>
Chemisches Element
Biologisches Material
Pharmazeutische Chemie
Lysin
Single electron transfer
Stoffwechselweg
Quelle <Hydrologie>
Eisenerz
Konzentrat
Primärstoffwechsel
Oligonucleotide
Karsthöhle
Computeranimation
Cyclo-AMP
Stratotyp
Gap junction
Hydrolasen
Testosteron
Polypropylen
Enzyminhibitor
Vorlesung/Konferenz
Toxikologische Analyse
Primärstoffwechsel
Cytoplasma
Interleukin 2
Biochemie
Oxidschicht
Stoffwechselweg
Gold
Ester
Hydroxylierung
Dimere
Fremdstoff
Chemische Affinität
Verhungern
Mannose
Arzneimittel
Krankheit
Erythropoietin
Periodate
Sulfate
Hydroxylgruppe
Chemische Biologie
Nucleotidsequenz
Screening
Typ 2
Somatotropin
Helix <beta->
Tyrosin
Süßkraft
Tyrosin
Abschrecken
Zutat
Allmende
Lysin
Funktionelle Gruppe
Tandem-Reaktion
Lipogenese
Molekülbibliothek
DNS-Doppelhelix
Zuchtziel
Guanin
Helicität <Chemie>
Weiche Materie
Estran
Oxide
Monoterpene
Blockcopolymere
Pharmazie
Steroidtherapie
Ader <Geologie>
Heparansulfat
Calcium
Histidin
Mucine
Zellwachstum
Oktanzahl
Methylprednisolon-aceponat
Molekulardynamik
Setzen <Verfahrenstechnik>
Rezeptor-Tyrosinkinasen
Pentapeptide
Zellwachstum
Bindungsenergie
Bindungsenergie
Chromatographie
Trometamol
Härteprüfung
Interferon
Oberflächenchemie
Gelchromatographie
Alpha-2-Rezeptor
Intron
Enzym
Reglersubstanz
Oxalate
Organische Verbindungen
Nucleotide
Reaktivität
Proteintoxin
Zelle
Fleischerin
Faserplatte
Ester
Konformationsänderung
Macrogol
Adenylatcyclase
Tonschiefer
Domäne <Biochemie>
Aminosäuren
Chemische Verbindungen
Aktivierungsenergie
Strahlenbelastung
Chemische Forschung
Sauerstoffversorgung
G-Protein gekoppelte Rezeptoren
Harnstoff
Filmscharnier
Estradiol
Untereinheit
Posttranslationale Änderung
Chemische Forschung
Erythropoietin
Alphaspektroskopie
Chemische Verbindungen
Freies Elektron
Rhodopsin
Proteinkinase A
Pille
Lagerung
Weiche Materie
Regulatorgen
Zunderbeständigkeit
Gesättigte Fettsäuren
Atom
Phytosterine
Biosynthese
Wasserlöslichkeit
Gelchromatographie
Tiermodell
DNS-Doppelhelix
Substrat <Boden>
Potenz <Homöopathie>
Metalloenzym
Komplexbildungsreaktion
Querprofil
Quellgebiet
Elektronenakzeptor
Valenzisomer
Steroidstoffwechsel
Azokupplung
Polyethylene
Nucleotide
Diacylglycerine
Rückstand
Tee
Wasserstoffbrückenbindung
Molekül
Oligomere
Chemischer Prozess

Metadaten

Formale Metadaten

Titel Lecture 18. Terpenes and Cell Signaling, Part 2
Alternativer Titel Lec 18. Introduction to Chemical Biology -- Terpenes and Cell Signaling -- Part 2
Serientitel Chemistry 128: Introduction to Chemical Biology
Teil 18
Anzahl der Teile 18
Autor Weiss, Gregory Alan
Lizenz CC-Namensnennung - Weitergabe unter gleichen Bedingungen 3.0 Unported:
Sie dürfen das Werk bzw. den Inhalt zu jedem legalen und nicht-kommerziellen Zweck nutzen, verändern und in unveränderter oder veränderter Form vervielfältigen, verbreiten und öffentlich zugänglich machen, sofern Sie den Namen des Autors/Rechteinhabers in der von ihm festgelegten Weise nennen und das Werk bzw. diesen Inhalt auch in veränderter Form nur unter den Bedingungen dieser Lizenz weitergeben.
DOI 10.5446/18877
Herausgeber University of California Irvine (UCI)
Erscheinungsjahr 2013
Sprache Englisch

Inhaltliche Metadaten

Fachgebiet Chemie
Abstract UCI Chem 128 Introduction to Chemical Biology (Winter 2013) Instructor: Gregory Weiss, Ph.D. Description: Introduction to the basic principles of chemical biology: structures and reactivity; chemical mechanisms of enzyme catalysis; chemistry of signaling, biosynthesis, and metabolic pathways. Index of Topics: 0:03:13 Cell Signaling 0:07:19 The 7 Signaling Pathways 0:09:41 Control Over Cell Differentiation Through Cytokines 0:12:04 Erythroproietin Signals Through the Jak-STAT Pathway 0:16:03 Chemical Control Over Cell Signaling Through Dimerization 0:22:25 Modification of Proteins for Better Properties 0:25:57 Growth Factor Signaling Through Cell surface Kinases 0:33:19 Sequential Phosphorylation 0:34:22 MAP Kinaase signaling 0:36:00 Peptide Binding Domains 0:38:32 Small Molecules in Cell Signaling 0:42:48 G Protein-Coupled Receptors 0:58:15 Vision Through Cis-Trans Olefin Isomerization 1:01:35 Ion Channel Signaling 1:03:31 Trimeric Death Receptors 1:04:38 Signaling by Diffusible Gas MOlecules 1:06:58 NO Causes Relaxation of Smooth Muscle in Blood Vessles 1:08:38 Chemical Biology: Review

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