The 2012 Nobel Prize in Chemistry was awarded jointly to Robert J. Lefkowitz and Brian Kobilka for studies of G-protein-coupled receptors, which are the portals by which information about the environment reaches the interior of cells and leads to their responses. About half of all drugs work by interacting with G-protein-coupled receptors.

The official Nobel Prize press release:

10 October 2012

The Royal Swedish Academy of Sciences has decided to award the Nobel Prize in Chemistry for 2012 to

Robert J. Lefkowitz
Howard Hughes Medical Institute and Duke University Medical Center, Durham, NC, USA

and

Brian K. Kobilka
Stanford University School of Medicine, Stanford, CA, USA

"for studies of G-protein–coupled receptors"

Smart receptors on cell surfaces

Your body is a fine-tuned system of interactions between billions of cells. Each cell has tiny receptors that enable it to sense its environment, so it can adapt to new situtations. Robert Lefkowitz and Brian Kobilka are awarded the 2012 Nobel Prize in Chemistry for groundbreaking discoveries that reveal the inner workings of an important family of such receptors: G-protein–coupled receptors.

For a long time, it remained a mystery how cells could sense their environment. Scientists knew that hormones such as adrenalin had powerful effects: increasing blood pressure and making the heart beat faster. They suspected that cell surfaces contained some kind of recipient for hormones. But what these receptors actually consisted of and how they worked remained obscured for most of the 20th Century.

Lefkowitz started to use radioactivity in 1968 in order to trace cells' receptors. He attached an iodine isotope to various hormones, and thanks to the radiation, he managed to unveil several receptors, among those a receptor for adrenalin: β-adrenergic receptor. His team of researchers extracted the receptor from its hiding place in the cell wall and gained an initial understanding of how it works.

The team achieved its next big step during the 1980s. The newly recruited Kobilka accepted the challenge to isolate the gene that codes for the β-adrenergic receptor from the gigantic human genome. His creative approach allowed him to attain his goal. When the researchers analyzed the gene, they discovered that the receptor was similar to one in the eye that captures light. They realized that there is a whole family of receptors that look alike and function in the same manner.

Today this family is referred to as G-protein–coupled receptors. About a thousand genes code for such receptors, for example, for light, flavour, odour, adrenalin, histamine, dopamine and serotonin. About half of all medications achieve their effect through G-protein–coupled receptors.

The studies by Lefkowitz and Kobilka are crucial for understanding how G-protein–coupled receptors function. Furthermore, in 2011, Kobilka achieved another break-through; he and his research team captured an image of the β-adrenergic receptor at the exact moment that it is activated by a hormone and sends a signal into the cell. This image is a molecular masterpiece – the result of decades of research.

Robert J. Lefkowitz, U.S. citizen. Born 1943 in New York, NY, USA. M.D. 1966 from Columbia University, New York, NY, USA.Investigator, Howard Hughes Medical Institute. James B. Duke Professor of Medicine, and Professor of Biochemistry, Duke University Medical Center, Durham, NC, USA.

Brian K. Kobilka, U.S. citizen. Born 1955 in Little Falls, MN, USA. M.D. 1981 from Yale University School of Medicine, New Haven, CT, USA. Professor of Medicine, and Professor of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.

Also see:

Cell Signalling Caught in the Act and Cell Signalling: It's All About the Structure, both by Lizzie Buchen

And videos of two 2010 Lefkowitz lectures:

Part 1 Seven Transmembrane Receptors

Part 2 Beta-arrestins

Podcast Transcription

Steve:       Welcome to the Scientific American podcast Science Talk, posted on October 10th, 2012. I am Steve Mirsky.

Lefkowitz:          Well, I'm thinking that this is going to be a very, very hectic day. I plan to go to the office. I was going to get a haircut but… which if you could see me, you would see it's quite a necessity, but I'm afraid that'll probably have to be postponed. It will be a pretty crazy day at my office.

Steve:       That's Robert Lefkowitz who received word very early this morning, Eastern Time, that he had and his former postdoctoral fellow, Brian Kobilka, had won the Nobel Prize for Chemistry. More from Lefkowitz in a bit. His phone connection was a bit dodgy, but you can make out what he was saying. Staffan Normark of the Nobel Committee for Chemistry made the public announcement. You'll also hear committee members Sven Lidin and Sara Snogerup Linse. Here's Normark.

Normark:  This year's prize deals with cells and sensibility. The Royal Swedish Academy of Sciences has decided to award the 2012 Nobel Prize in Chemistry to Professor Robert J. Lefkowitz at Howard Hughes Medical Institute at Duke University Medical Center, Durham, North Carolina, USA; and Professor Brian K. Kobilka at Stanford University School of Medicine, Stanford, California, USA. And the academy citation runs: For studies of G-protein-coupled receptors. Professor Sven Lidin will now give us a short summary in English; please Sven.

Lidin:         Thank you, Staffan. Boo! Do you remember the last time, you got really scared? The dryness of the mouth, the heart that skips a beat—these are signs that your body is getting ready for flight or fight. Adrenaline surges through the system, and it affects metabolism, circulation, respiration, muscles tonus and vision. It leads to an orchestrated response from the billions of individual cells that make up our bodies. It was known for a long time that adrenaline does not enter into the cells it affects, but an increase in the adrenaline levels on the outside of the cell leads to a response at the inside. A receptive substance, a receptor, was correctly assumed to be involved, but the nature of this receptor and how it acted remained a mystery for a long time. Now thanks to the work of Robert Lefkowitz and Brian Kobilka, awarded this year's Nobel Prize in chemistry, we know what this receptor looks like in the finest molecular detail. We also know that it's just one member of a huge family of receptors, the G-protein-coupled receptors or the GPCRs; we know the mechanism by which GPCRs function, and we know how that function is regulated. Now the communication between our cells is essential, not only in times of fear but in everyday life, and unbalance in this communication leads to unhealth. Now a large proportion, some say 50 percent, of all pharmaceuticals used today rely on action targeting GPCRs. So, knowing what they look like and how they function will provide us with the tools that can help us to make better drugs with fewer side effects.

Normark:  Thank you for these words, Professor Lidin. And now Professor Snogerup Linse, you will give a more detailed presentation of this year's prize.

Linse:        Thank you. G-protein-coupled receptors sit in the membrane. They tell the inside of the cell what's going on on the outside. Thanks to the studies by Robert Lefkowitz and Brian Kobilka, we know how these receptors are built, how they work and how they're regulated. There's a whole family of receptors that are built in a very similar way. They all have seven helices, spiral-like structures that go through the membrane, therefore they're also called seven-transmembrane receptors, 7-TM. In our body circulates a number of neurotransmitters and hormones—some of the names you may recognize, serotonin, histamine, adrenaline etc.—and these action via G-protein-coupled receptors. The molecule adrenaline binds to at least nine different G-protein-coupled receptors in our bodies and causes different responses in different organs. So when the heart and lung muscles are activated at the same time our digestion is shut down. The manmade molecule, beta-blocker, it's similar to adrenaline, yet different enough that it only binds to [a] subset of the adrenaline receptors, therefore it only affects certain organs. Indeed the G-protein-coupled receptors are the targets for about half of all pharmaceutical drugs made today; and these are used in treatment of conditions like high blood pressure, neuropsychiatric disorders, Parkinson's disease, migraine, gastric disorders, you name it—think of a disease and there is probably a medicine there affecting a G-protein-coupled receptor. So, the receptor sits in the membrane, and when a signal comes in the form of increased adrenaline concentration, the task for this receptor is now to tell the inside of the cell that this has happened; but it doesn't do so by letting adrenaline in, instead the receptor binds, each receptor binds one molecule of adrenaline in a pocket on the outside region and this leads to change in the shape of the receptor, so that it opens up a site in the inside where it can bind another protein, for example, a G-protein. The receptor is a little bit like a bundle of words. When the receptor is not activated the words are fairly parallel to one another, and on the inside of the cell there's really nothing to interact with. When a small molecule binds at the outside, what small changes in the structure propagates into much larger change on the inside with a G-protein combined. This is also the reason another small molecule can elicit very different changes on the inside, which then signals to other proteins on the inside and other signaling pathways. The complex is the active signaling unit. It is sometimes called a ternery complex, because three things are needed to come together: the hormone, the receptor and the G-protein. This has been known since middle of the 1980s, thanks to studies using, for example, radioactive  hormones, cloning work. Today, we know what this complex look like in near atomic detail. It's the result of three decades of dedicated biochemical work at the bench. The methods derived to be able to obtain this structure by crystallography have now also been used and are being currently used to make crystals of a large number of drug-important receptors to divider structures. This is very important knowledge in development of drugs, to obtain medications with fewer side effects. We have about one thousand different G-protein-coupled receptors in our body to be able to sense a huge number of different hormones, neurotransmitters and other signals. In our body, adrenaline can interact with nine different receptors and cause very different responses in different locations. G-protein-coupled receptors are also found on the outside of our body in the sensory cells—in our nose, in our tongue, in our eyes—and this allows us to sense our environment, to smell and taste and see. And now I really need a cup of coffee, thank you. Ah, thank you. Thanks to the G-protein-coupled receptors, I can now really enjoy this cup of coffee—the smell, the aroma, the beautiful serving, neurotransmitters hormones. Many G-protein-coupled receptors are active now, and thanks to the studies by Robert Lefkowitz and Brian Kobilka, I can also enjoy the excitement of knowing exactly in finest molecular detail what's going on in my body right now when many signals are passed over my cell membranes. Thank you.

Normark:  Thank you, Professor Snogerup Linse, and we will now see if we can get a hold of one of the two laureates. Do we have Professor Lefkowitz there with us on the phone?

Lefkowitz:          Yes, I am on the phone.

Normark:  Congratulations, and I['ll] tell you that we are sitting in the session hall here in Stockholm at the Royal Swedish Academy of Sciences, and we have around 80 to 90 persons from [the] Swedish and international press, and I know that they are eager to pose some questions to you; are you ready to take on these questions, Professor Lefkowitz?

Lefkowitz:          I am indeed.

Normark:  Okay, so please go ahead.

Victoria:    Good morning professor. My name is Victoria Dyring; I'm from the Swedish television. We're live on air right now. First congratulations—how are you feeling right now?

Lefkowitz:          I'm feeling very, very excited.

Victoria:    Could you tell us, how did you get this message?

Lefkowitz:          Well, I was fast asleep and the phone rang. I did not hear it. I must share with you that I wear ear plugs while I sleep, and so my wife gave me an elbow, and said, "There's a call for you, "and there it was—a total shocking surprise, as I'm sure many before me have experienced.

Victoria:    Have you any plans for today?

Lefkowitz:          Well, I'm thinking that this is going to be a very, very hectic day. I plan to go to the office. I was going to get a haircut, but… which if you could see me, you would see it's quite a necessity, but I'm afraid that'll probably have to be postponed. It'll be a pretty crazy day at my office.

Normark:  We have a question there?

Reporter: I have a question about these receptors: We were told just now that they are the targets of about half of the pharmaceuticals that the drug industry make[s]—what about them make[s] them so useful in medicine?

Lefkowitz:          Well, I think there are several things that make these receptors so useful in medicine. The first is that as you probably heard, there are a very large group of these receptors, and they serve as the gateway to the cells for many different neurotransmitters and hormones in our body. As a result, they are crucially positioned to regulate almost every known physiological process in humans. And, of course, as physicians what we need to do in cases of disease is to manipulate the activity of these normal substances like adrenaline, you've heard of, serotonin, dopamine. And I think [it's] the diversity of substances in our body that work through this mechanism that makes them so crucially positioned to be able to respond to drugs of various types.

Normark:  They have a question there.

Louise:      Hi, and congratulations Professor Lefkowitz. My name is Louise; I'm from the Associated Press. I'm going to ask you a very, very typical question that we always get when the prizes are announced. Did you expect to win this prize or not? Just tell me a little bit about if you've been anticipating it or not?

Lefkowitz:          That's a wonderful question. Let me start with the short term and the long term. In the short term, I was just commenting a few minutes ago about the fact that, if the committee has any questions about the extent to which their secrecy works, let me say, it does. I did not have a single rumor or inclination or clue of any kind, so I can assure you I did not go to sleep last night waiting for this call. So, that's point one. For the longer term, sure I think every scientist dreamed in the little recess of his mind that someday one would get a call like that, but it's more fantasy than anything else. So, did I expect to get it? No. Did I even have any inkling that it was coming? I would have to say no.

Steve:       Following the press conference, Nobel committee member Sara Snogerup Linse spoke briefly to an unidentified reporter.

Reporter: Sara Snogerup Linse, you are a member of the Nobel Committee in Chemistry. Brian Kobilka was actually a graduate student of Robert Lefkowitz as I understand sometime ago; was it in the '80s?.

Linse:        Yeah. As far as I know, he was a postdoctoral fellow with Robert Lefkowitz, and it was actually the two of them together that cloned the gene and sequenced the beta adrenergic receptor and found the homology of rhodopsin.

Reporter: They had actually, as they mentioned, a real Eureka moment in their life.

Linse:        Yeah. It was known at a time that there were several receptors, and it was known that they all signal on the inside of the cell using G-proteins—that [work] has been awarded before [with] a Nobel Prize—but they didn't know that the receptors, all the different receptors were looking the same, and when they got the amino acid sequence of the beta adrenergic receptor and saw the homology of rhodopsin they immediately understood that also the receptors in the membrane are built in the same way and function in the same way and that was a real surprise and Eureka moment.

Reporter: And even when the receptors were known before, nobody realized they are just the same?

Linse:        No and it may be difficult to understand that today when we're so familiar with structural and functional homologies, but we have to remember was this was back in the 1980s and not so many protein families were discovered this way.

Reporter: So this is what was the hard part of it?

Linse:        The hard part to obtain the sequence was a result of many years, almost a decade's hard work, to extract the receptors and get enough material to be able to sequence it.

Reporter: So, this is, kind of, laboratory work.

Linse:        Yes. Many of the discoveries behind this prize are hard laboratory work over many, many years; not giving up even if it takes two or three decades.

Reporter: This is also a little puzzling because the pharmaceutical drugs existed before the receptors were known to chemists or to medical doctors as beta blockers, for example, they have been around for [a] much longer time than the science of the receptors has been developed. How did they know to develop the drug?

Linse:        They probably didn't know. Many drugs that we use are discovered by serendipity, trial and error; so the difference for the future will be that now when we know what these receptors look like, we know about this aspect of bio-signaling, that different similar ligands can cause very different biochemical effects. That will now lead to the possibility to make new drugs with fewer side effects.

Reporter: I also wonder when we listen to this wonderful press conference and listen to the prize conference for [the] Nobel Prize in Medicine, how do you define the borders between chemistry and medical research?

Linse:        I think in modern science, the borders have been, not erased, but the borders are not as sharp anymore and both chemistry and medicine are molecular subjects today. Medicine is no longer just giving something to patients and observing what happens. Also medicine is a molecular field, and many great discoveries are really at the interface between the traditional subjects.

Reporter: We're talking about the research in the '80s, when Brian Kobilka was [a] postdoc at Robert Lefkowitz's laboratory, but the research still going on. What is the question today?

Linse:        Lefkowitz today is working a lot with this aspect of bio-signaling—the properties of receptors that make them able to respond to more than one kind of substance and giving different responses inside the cell.

Reporter: And Brian Kobilka?

Linse:        Brian Kobilka, I don't know exactly because the last the molecular structure, it came out as late as September 2011. And exactly what he's doing at the moment, I don't know, but after that structure came out, actually in the same [issue] of Nature he also studied the complexes with another method—amide proton exchange coupled with mass spectrometry—to confirm that, although he used so many tricks to get the receptor to crystallize in the active state, it still looks like the real active state that is not manipulated.

Reporter: So, it's still ongoing science?

Linse:        Yes, definitely. I mean, this is just the beginning of a huge field.