Drug Design, Structural Dynamics and Physiological Functions of G Protein-Coupled Receptors (GPCRs)

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Drug Design, Structural Dynamics and Physiological Functions of G Protein-Coupled Receptors (GPCRs)
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CC Attribution - NonCommercial - NoDerivatives 4.0 International:
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2018
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English

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Abstract
There are 826 G protein-coupled receptors (GPCR) in the human proteome, which regulate key physiological processes and have therefore long been attractive as drug targets. With crystal structure determinations of more than 50 different human GPCRs during the last decade, an initial platform for structure-based rational design was established for drugs that target GPCRs. The principal method used for our own research is nuclear magnetic resonance (NMR) spectroscopy in solution, which is one of the key approaches for expanding the crystal structure platform with dynamics features of GPCRs at near-physiological conditions. In this context it is of special interest that NMR measurements can be performed without extensive modifications of the GPCRs, such as those used to facilitate crystallization, i.e., by amino acid replacements and/or fusion with other proteins. In my lecture I describe strategies for the use of NMR techniques with GPCRs, which will be illustrated with projects where results obtained with X-ray crystallography or cryo-electron microscopy (cryo-EM) have been complemented with NMR investigations in solution, and discuss the impact of this integrative approach on GPCR biology and drug discovery. References Liu, J.J., Horst, R., Katritch, V., Stevens, R.C. and Wüthrich, K. (2012) Science 335, 1106-1110. Biased signaling pathways in β2-adrenergic receptor characterized by 19F-NMR. Eddy, M., Lee, M.-Y., Gao, Z.-G., White, K.L., Didenko, T., Horst, R., Audet, M., Stanczak, P., McClary, K.M., Han, G.W., Jacobson, K.A., Stevens, R. and Wüthrich, K. (2018) Cell 172, 68–80. Allosteric coupling of drug binding and intracellular signaling in the A2A adenosine receptor.
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a year. it's great to be eating go again. and i'd known to thank all of you michael eat and students fuller old the in pulled said i.d.c. for so far this week.
subtitle old my toll is focused on the p.c. arts cheap wrote in couple the sept there's a.
this is not new for you all of us left kaulitz who'll discovered g.p.c. arse.
gave you the marble those surveyed also history. and so latest developments in the field so i don't need to introduce the subject what i want to do and is favorable situation is to give you an impression of more structural biology.
can do in a rapidly evolving field which also find an incredible breath of practical applications is specially in drug discovery and to discern so it's a problem that be. by your physicists face of his diet. the p.c. are as you see here schematic drawing of sirte seven france membrane deal he says. one. well i'm told to. the screen should help me to point b l a. the yellow shape his colleague been in the so-called or so stary. finding site than that three trucks spined on the outside hopes the cell membrane and as a signal across the cell membrane over a distance of about thirty young stearns to see interest still the party protease this is typically classify. but as an hour stereo system say that now an analogy to an enzyme see active side would be on the in their silver surface and see a fake still is certain on strums away under signal is transmit. it did across the stations and that's what we are trying to understand we try to understand how it is possible that he's a loss to wreak signal transmission or kurds what's a structural bases these for this and the whole web. in contrast to previous lefkowitz g.p.c. art has not been my project for a very long time i received as was mentioned i receive my nobel prize for have been.
use and them art to study proteins and nucleic acids and and this important point in contribution from our research is that they can get three dimensional stroke use of protons and nucleic acid.
it's a good time in a comic resolution by an m.r.i. in so you shun now you realize that.
a word proteins are active in contact with a.q. solutions or day argument is solved in a chris media and so the thirty's olds so that we can obtain basis approach can be very close to his old said people tea and. physiological conditions now m.r. stands for nuclear magnetic resonance it could stand for no more research it could also stand for no meaningful results but it is nuclear magnetic resonance i think a taste.
point i want to digress a little bit to indicate to students in bought surroundings we started this verdict. the structural biology became an official high level part of natural sciences when it's a nobel prize in nineteen sixty two was awarded to this group of people we see from left to right more.
this bill killings max payloads francis crick john steinbeck that's a literature laureate him was soon and chong can do.
a mom d.'s value of course you know is heard this prize was given on the one hand for the discovery also d.n.a. double helix on the us in hand for the determination of so city dimensional structure of approach. putting them in him a global in an unrelated molecule myoglobin maxted route who is the second person from the left on this picture of balsa deeley leading structural biology. for decades after receiving the nobel prize in nineteen sixty two and the atmosphere is it that term was present and the rich be would start to develop and as a technique is well represented by.
i disclosed patient by match to roots of the jaipur now all in nineteen thirty six the secret of life lies in to structure of proteins and there is only one way of solving it and that is by takes a day to restore growth. we have now of course that asks for competition of do see it is very much easier to take could ideas from most use and then compete against if you have your own ideas you cannot compete against your ideas that would be sort of stupid.
it but so you have to get competitive and competition has been part of my life early on.
the in twenty fifteen an h e r to call included taste pictures of myself training high jumping in switzerland to an actual in the federal school of sports in near b.n. and the sea so i started.
to collect material for an age to debut already when i was seventeen years old. the.
structure of hemoglobin a time when beirut and can do shared a nobel prize for this achievement. looks like this no individual atoms could be seen and heard was actually a lot of possibilities for us to messages to get into it and i'd not going to talk about is today but i my first major project was to study human. globe in and it was immediately possible to use and them are in search ways that we would see individual atoms that the beyond so resolution of sickly still structure and i get very close relations with max spilt ever since the database. in the late nineteenth sixty's and the until the bell into two thousand. it is also important to keep the competitive spirit over a long time you see this picture is taken by peter batch in two thousand and fifteen and i'm still trying to keep the competitive spirit up and i'd like to illustrate to you.
to base the next projects that i'm going to describe same portman's of have been have been on the ball for a long time and the life of a scientist and that the same time i want to illustrate what at first time vote not be so last time and it's like she.
how important it is to integrate results from different techniques when you try to solve a particularly problem. now when professor left call it was just discovering the p.c. arse in the early nineteenth seventy's.
the bird perched on lincoln's to g.p.c. hours without knowing that said our g.p.c. ours and i show you a year to pick should that comes from sir tom blow dale a crystal local food who was able to determine the stroke should. of one of same portly conformity p.c.r. namely flu could go on and unfortunately it seems certain a screen doesn't verdict so i cannot point. the in to have to send did you see it the younger lead story she is this is a crystal structure that was determined by don't do and they'll and they consist of a primary aggregate of city molecules of flu could go. i mean no pain they stood should home. hypothesize that this made it for that was indeed present in old body that did to dissolve in two bombers would also be for the alpha it's really cool the same as a molecule balls in the dry married for such a cool. it's an easy bind to the membrane surface as an alpha helix ordered to dissolve into a random coy at that point we started to study says a molecule base the an m.r.i. and the first scene was so that we could show that. but bennett is the sole ft involved do it is not at all healy call that it is random coyle uncontained is one short piece of spatial structures that this will be fine and that is in the positions from twenty long to twenty five.
five and you can see such there is a final again and the rate of land and sees for his sandwich and that's the only stable structured in the anti-smoking q next we did study is a molecule this shortfall in peptide well it is pont two.
l.a.p.d. surface in detergent my cells and we found out that it is not feel the call is hypothesized on the basis of the crystal structure that there is only a short piece of felix again from the residues twenty to twenty seven and thirty main do.
it also molecule is in a random coin ford and.
this is just a detail this is a very first or should that pulls it is that was determined to tighter solution by an m r be finished this would be nineteen eight the city.
now it's actually certainty years later i started a new project in malibu oratory in shanghai and we study no sainted action of local goal was simple could go on to set the rich as a g.p. see art so this gives incredibly nice possibilities week. the study said the response of sixty p.c. on the cheap wrote in beat addressed in to see interaction of silicon based he also stayed excite p.c. outside of city said it under same time we can study what happened to serve a lake in. to the two of them. polly peptide lake and when it interacts with a receptive now we started to study this brought this system in twenty search team and the face is still too early to talk about that it takes a long time to develop such a system for structural biology. we have actually very encouraging results but for various reasons i'm not supposed to present season to mow so i will talk about two or three receptions and will not see his research receptor said it was a mainstay in the office. it left coates word namely peter to a yard and i use his scheme to indicate to you how we approached by your physical studies of these g.p.c. dollars what you see here is the scheme that shows. on the vertical axis so by your logic corresponds against different league hints that are applied in increasing concentration from left to ride on the only central axis and you have act in a state you have seen a of. for that means of so receptive without delay compound or recent and type in a sponsor that will enrich debates are receptive and then you may have an inverse agonist and so are you see also see expression basal extended the which in this scheme. his face the biological response units are you a response to news now we may have the p.c. ours have a base so much diversity of siro we may have t.p.c. odds with each other based solar activity so i corresponds to play. your certain percent of some maximum activities that you can obtain this unhappiness and basis basics introduction i now want to describe to you aware upload judge you see here on the left the schematic growing of peter to a you. god so the seven trance membrane helix structure of the race g.p.c. art. and it's s c two six pfeiffer to lower left leg and it was where it says see the city to seven which is somewhere in the middle it's a bold them be inserted labels that we could observe by and them are these are fluent in labels. there is no floor in in this whole system so that we can observe these probes without interference from the biological material and we would send us a small library of late in its big shot all drugs news i'm inclined bottle always so. the verse because it has been extensively used for doping of being competitive sports is by showing by very clifton's so on and you see that facing food is in worst i can taste sitting foods of the neutral antagonist it includes act in a state run it also includes. biased agonists which word extensively this caused by professor lefkowitz so we will go be would study these articles in ten americans and the mood in our study service palms of sows fluid impose on to intercell the surface to serve a variable. all. every to see also lincoln's that out on thirty storms away and these are said all data which i like to show just to let you see that the results can be certain of what you can see is out in each for each year.
it's easily kuntz owns all left for the position city to seven that is one of the probe's on the right four to six five that scioscia probe there are always to hardly resold peaks and you can see even and they said all data sets a relative in ten. city between the two peaks shifts from left to right from the right to left depending on the efficacy of the.
leg in india now his interpretation of the data you have year in the center it says a poll on the right schematic drawing have to have so he always says in the cheap p.c.r. helix aches and felix seven and we use your. room based on data and only richard out signaling to the jeep loathing cause primarily through the league six and signalling to arrest in those but i made only salou helix seven and that's where all the roadside. located now and we look at corus all starts or to growing in the upper left and the spectrum is shown here a bit u.c. always a deadline and the blue line is so we call this the contribution of suspects the room where we can determine said relative. its intensity is also to peak said that overlap of when we have an inverse i can is a big hill transmission to those signaling pathways when we have to fall agonist of the open search and also for those interactions. and then we have a biased antagonist we close star into cheap protein and tied like peter dressed in his opened and visit by a skype in his of the opens a beat adjusting channel and reduce the transferred to the cheap wrote in china now it's important. up and sing to be seen here which cannot be seen by end year submissive of these that we have to confirmations in actual idiom of they are here it's the same time and never do we have one hundred percent of the active like state or of see inactive like steak. and it is so possible start additional interactions for example of his jeep floating the speaker christine can first of shifty actually pretty on to be near one hundred percent activation orders to be close it to inactivation so we have here a highly. the dynamic those system so i can respond to the needs of some moment when thirty p.c. oddities functioning in our body and that is before be looked at many of circus surrounding the fake effects to save so i can also play the old. in this case. now i want to show to you how important it is that peter to a yard was started not only by crystallography but also by and them are an increase top you feel.
the. receptive was used was a sociable promoting the for tell lies aside and you see that to t. ford allies a sign that so blue shape has almost the same size as sixty p.c. are what we now have studied was how these functions related actual it. area are affected by the fusion of this so ubel protein into our own of say intercell oops dog happens once you have used the for sale in sexual a bloom is completely blocked and may have.
throughout his sensually one hundred percent stiff state going through a cheap bloating so dysfunctional related confirmation will actually be on is completely abolished with the preparation that was used for crystallography i think it's a. very convincing the demonstration of sim portman's of integrate if you use of multiple meeks and now i'm changing to second or she p.c. art that i want to discuss with you. they say see a to a a yard to add in all seen receptive and this is an overturned published that survey i mentioned the name of fuel costs so charts and thought the are now danko what we did here was to engineer.
group in two says into those malek she intercell live surface where sos big thurs circles are again we used floor in an absurd say fact of variable lincoln's on these floor in marshes.
here is a library of lake in such be used one or so's you have probably enjoy this morning it's cough a in which words as an antagonist for aid to a yard to important point that i want to make his side sees the front again aced and diffident and pattern. this served very different chemical stood just but say all it's the same spectrum in our would n.m. are expected on the left you have the antagonist take strong features to confirmations in actually be on in the administrators storm we have city. confirmations and now we can take see a perform at in action is so we go from to enact expected on tuesday actually flight spectrum and then returned to replace the agonised is a most strongly tidying antagonised and to go back to see inactive. spectral important saying here is that wide taipei to a yard has essentially siro basal activity and i knew now look at the peak which is between twelve and fourteen ppm and it's completely gone in to enact a form. see this is a yellow peak before showing that indeed we have it in hand if there is no residual activities that we can detect now we take a deep recession related g.p.c. our bases single amino acid a place in all seriousness and give on. ms allen in this form is known to have significant basal activity and immediately see that p four is present in what is supposed to be she actually afford so we can we have here said all actually pretty awesome between different in. such different different active forms of and of course we want to know wall serve exchanges between the two you hear you i show just as an illustration spectrum of see active like ford and you see is that the rate. of exchange between the warm and key to this is a peak from city actually flight for the two from the inactive like for the slow to about twenty his story is relatively fast twenty around twenty two second whereas six. change between the von from the inactive for them and p. for the ford from the axe to form is very slow lesson bomb to section of so we have a very high the have a very high activation died a year between see also all have actually flight shape their states. if and and also mobile of inactive like states that is intrinsic to the t.p.c. odd before it interacts with his partner proteins so that are of course important in the course of to follow up reactions.
now we have only be have introduced is flawed in labels and that gives us only a few points to observe now we have succeeded in expressing this particular t.p.c. are in the sharper stories for years of a word for.
two people and the taste point now we are able to first to show that it took us a full activity of some material that was expressed is a traditional message from so lefkowitz laborde tory this as it's night and we can now produce. millie crime quantities of these receptive six and many large number of the area in for themselves or is it and in the shot in the yeast we can now labels approach in this nitrogen fifteen hours to go under his duty. field and as a result using the techniques that be introduced about twenty years ago rose a france worst relaxation optimize spectroscopy we can now get the spectrum was hundred soviet solved lights and we can use a sin to. always make can use the whole spectrum to check out the global structure also molecule is always preserve when be the vendee generated variant and then be of belly soul of the lines in the two a square started. outlined the one hand sees oilers series ripped off and end all an age groups on the years around the backbone twice in a managed to use and then be replaced one and long each trip to fan base title sane and you can see your best see it on the right side is secure. all sections of the pictures that is marked by a nice to take disappears after you've replacing rate of tape to find his tyler sane and so we have won by of on the science of peaks we did the same for eight license and now we have observation points across.
else entirely molecule storm the intercell the surface seuss the center of somali killed to see extra sell the surface and i want to point out to resit use one is the fifty two the study just fifty two which is known to be so the. hello story. cork in the molecule so we will destroy this i was staring scented in check what happens and then we have a profound two four six which has been referred to as vocal smidge ripped off and that's been found just been reported to be of the. make sure that importance during the activation pros says of cities it so what comes out when we look at cities bones to variable broke effort to see then we get no response of want to see extracellular surface and to get the structural responds all over city.
the sept did all the way from zoellick in pointing site to see intercell the surface of here are just a few examples of how clear could see some responses are when be very specific ethnic to see also lake in india or sustain excite.
and the year to beat is effectively see in the four days topples makes the report found that we get the chemical shifty florence again identified kezer stars on the ride of almost one party million and we know what happened said we are saying trifle tovey know exactly what happened said.
this year ancient of seattle matic gains in the central city set but now things are very last my time is or by taking next there are many to describe to you what we did with regards to the study his own servers structural basis of see others terry.
signaling from see extracellular to see intercell new surface on the extreme left you have suffering should know. but she p.c.r. where you find only indeed to get cheap wrote in signalling then be replaced so he sent two of the i was scary switch which is or negatively charged rated you visit neutral analog and we get no signaling sue so the question. question is why do we know cut signaling sue and this question to answer this question is important because eighty six percent of all class a cheap easy ours of content is bad because sit in this position.
so when he makes its replacement we again get a huge change in the dock also age. the resonance and just look at so left side what happens is that when be destroy say i was very strange because no signaling down to see intercell the surface all the signalling is pushed back.
and structural changes are seen only above w o two for six and also weigh up in to say it's just sell the surface of so what we have shown is that the signaling to see other states which is. killed when be replaced or negatively charged rated you and so signal is actually push back to see outside of cell and all the dynamics of certain as it used on the surface on the interest sell the surface is stopped. and we see only a single richard surface stroke she whereas in the active side be alive. the dynamic actually per year between all the sides certainly can observe so in summary of the i've been able to show up.
activity of the piece yards cannot be understood simply by looking at the meeting structures of the active or seen active forms be of local confirmation of polymorphous of which make it a highly dynamic system such an adult. now those are deeds in any given situation we can show that clicking if a fee to see his belated not to stated structural changes but to shifts in confirmation electoral it korea got a bold and now this is in contrast to so the soul. what's up paying for all my client or e.m. which also shows that there are multiple different confirmations country can measures exchange between the ska information's we don't just sampled the use of different structures and of course are on a continuing on. we can get information on all of these properties from interactions with his exodus a leak instantly see interest simulate the action partners thank you.
i have.
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