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Lecture 18. Terpenes and Cell Signaling, Part 2

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Title Lecture 18. Terpenes and Cell Signaling, Part 2
Alternative Title Lec 18. Introduction to Chemical Biology -- Terpenes and Cell Signaling -- Part 2
Title of Series Chemistry 128: Introduction to Chemical Biology
Part Number 18
Number of Parts 18
Author Weiss, Gregory Alan
License CC Attribution - ShareAlike 3.0 Unported:
You are free to use, adapt and copy, distribute and transmit the work or content in adapted or unchanged form for any legal and non-commercial purpose as long as the work is attributed to the author in the manner specified by the author or licensor and the work or content is shared also in adapted form only under the conditions of this license.
DOI 10.5446/18877
Publisher University of California Irvine (UCI)
Release Date 2013
Language English

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