Nobel Prize in Chemistry 2012: Lefkowitz, Kobilka and G-Protein-Coupled Receptors

This note covers the Nobel Prize in Chemistry 2012: who won it, what G-protein-coupled receptors are and how they let cells sense hormones, light, smell and taste, how the discovery of these receptors unfolded over four decades, why the work matters for medicine, and quick facts for exams.

What was the Nobel Prize in Chemistry 2012 awarded for?

The Royal Swedish Academy of Sciences awarded the prize jointly to Robert J. Lefkowitz and Brian Kobilka "for studies of G-protein-coupled receptors". This is the exact citation given by the awarding body.

In plain words, the two scientists worked out how a huge family of molecular "receivers" sitting on the surface of our cells manage to sense chemical and physical signals from outside, such as hormones, odours, flavours and even light, and then pass a message to the inside of the cell.

The official name of this award is the Nobel Prize in Chemistry, and it is one of the original five prizes established in Alfred Nobel's will, administered by the Royal Swedish Academy of Sciences.

Before this work, scientists had known for decades that something on the cell's outer wall must be catching hormones like adrenalin, but nobody had isolated that "something" or understood how a signal arriving outside a cell could change what happens deep inside it.

Lefkowitz and Kobilka's research answered that question for an entire class of receptors now called G-protein-coupled receptors, or GPCRs.

Who are the laureates?

Robert J. Lefkowitz

Robert J. Lefkowitz was born on 15 April 1943 in New York, NY, USA. At the time of the award he was affiliated with the Howard Hughes Medical Institute, USA, and Duke University Medical Center, Durham, NC, USA. He received one half of the prize.

Lefkowitz trained as a doctor at Columbia University and began his receptor research in 1968, while doing his military service at the National Institutes of Health during the Vietnam War era.

He later built his research team at Duke University, where he has worked since 1973.

His key contribution was proving, for the first time, that a hormone receptor was a real, physical molecule that could be tracked and isolated, and later leading the work that cloned the gene for the adrenalin receptor.

Brian Kobilka

Brian K. Kobilka was born on 30 May 1955 in Little Falls, MN, USA. At the time of the award he was affiliated with Stanford University School of Medicine, Stanford, CA, USA. He also received one half of the prize.

Kobilka trained in medicine at Yale University and worked in hospital intensive care before joining Lefkowitz's team at Duke in the 1980s. He devised the method that finally isolated the gene for the adrenalin receptor, which revealed its structure.

He then moved to Stanford, where in 2011 his team produced an image of the receptor in the exact instant it is activated by a hormone, a result the prize committee called "a molecular masterpiece".

What problem were they trying to solve?

Every cell in the human body is wrapped in a membrane, a thin wall made of fat molecules, that keeps its inner chemistry separate from the outside world.

For the body to function, cells still need to know what is happening outside: whether a stress hormone has flooded the bloodstream, whether a nearby cell is sending a chemical message, or whether light has struck the eye.

Scientists at the end of the nineteenth century, studying the hormone adrenalin, noticed that it sped up the heart and raised blood pressure even when the nervous system of test animals was disabled.

This suggested cells must carry some kind of receptor, a "receptive substance" on their surface, able to sense the hormone directly.

In the 1940s the American scientist Raymond Ahlquist proposed that there were at least two distinct types of receptor for adrenalin, which he called alpha and beta, based on how different organs responded.

But for decades the receptors themselves could not be found, isolated or pictured; as Ahlquist himself wrote, they remained "an abstract concept conceived to explain observed responses of tissues".

The core difficulty was that receptors are few in number and are buried inside the fatty cell membrane, which made them extremely hard to extract without destroying them. It is this long-standing mystery, how a cell "feels" its environment, that Lefkowitz began to attack from 1968 onward.

How did Lefkowitz first detect a receptor?

Lefkowitz's approach, suggested by his supervisor at the National Institutes of Health, was to attach a radioactive iodine isotope to a hormone and then track where the radiation went when the hormone touched a cell.

If the hormone's binding to the outside of the cell could be shown to trigger a known chemical change on the inside, that would prove a genuine, functioning receptor had been found.

1. Lefkowitz began by labelling adrenocorticotropic hormone with radioactive iodine and testing it against adrenal gland tissue.
2. After about a year without success, he began to see results and published papers in 1970 describing an active receptor.
3. He then moved his research to Duke University and shifted his focus to receptors for adrenalin and noradrenalin, known as adrenergic receptors.
4. Using radioactively tagged beta blockers and other substances, his team refined their methods until they could extract adrenergic receptors from biological tissue in working form.

Meanwhile, other researchers were mapping what happens once a receptor is triggered. It was already known that receptors on activation switch on a G-protein inside the cell, which then sets off a chain of chemical reactions that change the cell's behaviour.

This is why the whole receptor family later came to be called "G-protein-coupled receptors".

Sketch a cell membrane as a double layer of fat molecules with a receptor protein threaded through it seven times.

On the outside, draw a hormone molecule docking onto the receptor; on the inside, draw a G-protein next to the receptor, with an arrow showing it being switched on once the hormone binds.

How did Kobilka's gene-hunting reveal a whole receptor family?

In the 1980s Lefkowitz's group decided to try to find the actual gene that codes for the beta-adrenergic receptor. A gene works like a blueprint: if they could read it, they would learn what the receptor protein was built from.

Kobilka, newly recruited to the team, took on this technically difficult search, likened by the committee to "trying to find a needle in a haystack" within the human genome.

Kobilka devised a creative method that succeeded in isolating the gene. When the researchers analysed its code, they found the receptor protein was built from seven long, fatty spiral strings, called helices, that thread back and forth through the cell membrane seven times.

This was strikingly similar to the structure of rhodopsin, a light-sensing receptor already known in the eye.

Lefkowitz described this resemblance as a "real eureka moment". He already knew that both adrenergic receptors and rhodopsin worked through G-proteins, and that around thirty other receptors did too.

The conclusion: all these receptors belonged to one large family, sharing the same seven-helix shape and the same basic way of working, even though the signals they detect range from light and smell to hormones and taste.

This family is now called G-protein-coupled receptors (GPCRs), and about a thousand human genes code for them.

How was the receptor finally imaged in action?

After isolating the gene, Kobilka moved to Stanford University School of Medicine, where he set himself the goal, seen by many as unreachable, of producing an actual image of the receptor.

Proteins are far too small to see with ordinary microscopes, so scientists use X-ray crystallography: they pack the protein into a tightly ordered crystal, fire X-rays through it, and work out the protein's shape from how the rays scatter.

This was especially hard for GPCRs because they sit inside the fatty membrane rather than dissolving in water, and because they are naturally mobile, moving as they transmit signals, while a crystal requires the molecule to stay almost perfectly still. It took Kobilka more than two decades to solve these problems.

In 2011, his team finally captured an image of the β-adrenergic receptor at the exact moment it is transmitting a signal: a hormone bound on the outside, and a G-protein attached on the inside.

The image, published in the journal Nature, showed that when the hormone binds, the inside of the receptor opens up, in the committee's words, "like a bouquet of flowers", creating a gap where the G-protein can attach.

Draw two versions of the same seven-helix receptor side by side. In the first, show it closed with no hormone attached.

In the second, show a hormone docked on the outside and the inner helices spread apart, opening a pocket where a G-protein attaches.

How did the discovery unfold?

The story of G-protein-coupled receptors stretches across more than four decades, moving from a vague suspicion that cells must have some kind of sensor to an atomic-level picture of that sensor caught in the act of signalling.

It began at the end of the nineteenth century, when experiments on adrenalin convinced scientists that cells carry a receptive substance on their surface, even though nobody had found it. Decades later, Lefkowitz's radioactive tagging method finally made a receptor visible and trackable. Kobilka's gene-hunting in the 1980s then exposed its seven-helix shape and its kinship with the eye's light receptor, rhodopsin.

The final chapter came in 2011, when Kobilka's team at Stanford produced the long-sought image of the receptor at the exact moment it is switched on, a result the Nobel committee described as "a molecular masterpiece". The table below sets out the main dates.

Seen as a whole, this timeline shows a field that advanced in large, separated leaps rather than smooth, continuous progress: a breakthrough in tracking, then a long gap before the gene was found, and then another long gap of over two decades before the receptor could actually be imaged while working.

Why does it matter?

G-protein-coupled receptors are not a rare curiosity; they are the single most common way the body senses its surroundings.

The prize committee noted that about a thousand human genes code for such receptors, covering senses for light, flavour, odour, adrenalin, histamine, dopamine and serotonin.

Roughly half of them respond to smell as part of the olfactory system, and others handle hormones, taste and vision.

Because so many bodily processes run through GPCRs, the committee stated that around half of all medications achieve their effect through these receptors.

Examples include beta blockers (which calm an overactive β-adrenergic receptor and are widely used for heart conditions and high blood pressure) and antihistamines.

Understanding the exact three-dimensional shape of an activated receptor gives drug designers a far more precise target, since they can now see what the receptor's "open" shape looks like and design molecules that fit it.

The work also showed that a single receptor can recognise more than one hormone, and that receptors can act through pathways other than G-proteins, for instance via proteins called arrestins.

This is why the scientific background from the Nobel committee notes that "7TM" (seven-transmembrane) is becoming the preferred name for the family, rather than restricting it to "G-protein-coupled".

Open questions remain: over a hundred of the roughly thousand known receptor genes still have no identified purpose.

How does this connect to what you study?

GPCRs sit squarely in the overlap between chemistry and biology, which is why a chemistry prize was awarded for work that is really about how cells behave.

If you study the structure of cell membranes, you will recognise the phospholipid bilayer, the fatty wall that separates a cell's inside from its outside, and through which the receptor threads back and forth seven times.

If you study hormones in human physiology, the adrenalin story in this note is a direct illustration of the general principle: a chemical messenger released outside a cell can change what happens deep inside it, without ever crossing the membrane itself. For example, in the body's stress response, the adrenal gland releases adrenalin, noradrenalin and cortisol that raise heart rate, open the airways and flood the blood with fuel for the muscles.

The idea of a protein changing its three-dimensional shape when a smaller molecule binds to it, seen in the receptor opening up "like a bouquet of flowers" when a hormone docks onto it, is also a useful bridge to enzyme-substrate interactions taught in biochemistry, where binding likewise triggers a shape change that drives a reaction.

Students who go on to study pharmacology will meet GPCRs again directly, since around half of all medications, including beta blockers and antihistamines, work by acting on this receptor family.

Quick facts for exams

The Nobel Prize in Chemistry 2012 was awarded jointly to Robert J. Lefkowitz and Brian Kobilka, announced on 10 October 2012 by the Royal Swedish Academy of Sciences, each receiving one half of the prize.

The citation reads "for studies of G-protein-coupled receptors". Lefkowitz, born in New York, USA, in 1943, was affiliated with the Howard Hughes Medical Institute and Duke University Medical Center at the time of the award.

Kobilka, born in Little Falls, Minnesota, USA, in 1955, was affiliated with Stanford University School of Medicine.

Their combined work revealed how GPCRs, a huge family of cell-surface receptors with a shared seven-helix structure, sense hormones, light, smell and taste, and how roughly half of all medicines act through this receptor family.

Note: Source. The prize facts in this note are from the Nobel Prize's official site, nobelprize.org.

Glossary

• G-protein-coupled receptor (GPCR) — a cell-surface protein, built from seven helices crossing the membrane, that senses a signal outside the cell and passes a message inside via a G-protein.
• Receptor — a molecule on or in a cell that recognises and binds a specific signal, such as a hormone.
• Hormone — a chemical messenger released into the body that changes the activity of target cells, such as adrenalin.
• Adrenalin (epinephrine) — a hormone released by the adrenal gland that raises heart rate and blood pressure during stress.
• G-protein — a protein inside the cell that is switched on by an activated receptor and starts a chain of chemical reactions.
• Helix — a spiral-shaped section of a protein chain; GPCRs have seven helices crossing the cell membrane.
• Plasma membrane — the fatty, phospholipid wall surrounding a cell that separates its inside from the outside.
• Rhodopsin — the light-sensing receptor in the eye, found to share the same seven-helix structure as adrenergic receptors.
• X-ray crystallography — a method of working out a molecule's three-dimensional shape by passing X-rays through a crystal of it and studying how they scatter.
• Beta blocker — a drug that blocks the beta-adrenergic receptor, used to treat heart and blood pressure conditions.
• Arrestin — a protein that can interact with an activated receptor independently of G-proteins, forming an alternative signalling route.
• Seven-transmembrane (7TM) receptor — an alternative name for GPCRs, based on their seven membrane-crossing helices.

Common errors and misconceptions

• Misconception: The two laureates worked entirely separately on different problems. Correct: Kobilka was recruited into Lefkowitz's research team at Duke University in the 1980s, and the gene-isolation work that led to discovering the receptor family was done together before Kobilka later moved to Stanford.
• Misconception: G-protein-coupled receptors only sense hormones like adrenalin. Correct: The same family also detects light, odour and flavour, since the light receptor rhodopsin and taste and smell receptors share the same seven-helix structure.
• Misconception: The receptor was photographed with an ordinary microscope. Correct: It was imaged using X-ray crystallography, a technique that infers a molecule's shape from how X-rays scatter off a crystal of it.
• Misconception: Hormones pass through the cell membrane to deliver their message. Correct: The hormone binds only on the outside; the signal crosses the membrane through a change in the receptor's own shape, not by the hormone itself entering the cell.
• Misconception: Only a handful of receptors belong to this family. Correct: Roughly a thousand human genes code for G-protein-coupled receptors.
• Misconception: The receptor's structure was found quickly once scientists started looking. Correct: It took decades, from Lefkowitz's first radioactive tracing in 1968 to Kobilka's activated-receptor image in 2011.

Exam-style questions with model answers

Q1. For what work were Robert J. Lefkowitz and Brian Kobilka awarded the Nobel Prize in Chemistry 2012? [2 marks]

1. They were awarded the prize "for studies of G-protein-coupled receptors", a family of cell-surface proteins that sense signals from outside the cell.

Q2. Describe how Lefkowitz first succeeded in detecting a hormone receptor. [4 marks]

1. In 1968, Lefkowitz attached a radioactive iodine isotope to a hormone, initially adrenocorticotropic hormone, so that the radiation could be used to track where it bound on a cell.
2. After about a year of effort, he showed that this binding to the outside of the cell corresponded with a known chemical change happening on the inside, proving a genuine functioning receptor had been identified rather than an abstract idea.
3. He published these findings in 1970 and then moved to Duke University, where he extended the method to adrenergic receptors using radioactively tagged beta blockers.

Q3. Explain how the discovery of the gene for the beta-adrenergic receptor led to the idea of an entire family of G-protein-coupled receptors. [6 marks]

1. In the 1980s, Lefkowitz's team wanted to find the gene coding for the beta-adrenergic receptor, since a gene acts like a blueprint showing how a protein is built.
2. Brian Kobilka, newly joined to the team, devised a method that succeeded in isolating this gene from the human genome, a task the Nobel committee compared to finding a needle in a haystack.
3. When the gene's code was analysed, it showed the receptor was built from seven long, fatty spiral helices that cross the cell membrane repeatedly.
4. This seven-helix shape closely matched the structure of rhodopsin, the light-sensing receptor already known in the eye, despite the two receptors detecting completely different signals.
5. Lefkowitz realised this was no coincidence: since both receptors, and around thirty others already known, worked through G-proteins inside the cell, there had to be a whole family of receptors sharing this same structure and mechanism.
6. This family is now known as G-protein-coupled receptors, with around a thousand human genes coding for members that sense hormones, light, smell and taste.

Q4. What did Kobilka's 2011 imaging work show, and why was it difficult to achieve? [4 marks]

1. Kobilka's team used X-ray crystallography to capture an image of the β-adrenergic receptor at the exact moment a hormone was bound on the outside and a G-protein was attached on the inside.
2. This was difficult because GPCRs sit inside the fatty cell membrane rather than dissolving easily in water, and because they are naturally mobile as part of how they transmit signals, while crystallisation needs the molecule to stay almost still.
3. It took Kobilka more than two decades to overcome these obstacles and achieve this result, published in Nature in 2011.

Q5. Name both affiliations Robert J. Lefkowitz held at the time of the award. [2 marks]

1. Robert J. Lefkowitz was affiliated with the Howard Hughes Medical Institute and Duke University Medical Center, both in the USA; Brian Kobilka was affiliated with Stanford University School of Medicine alone.

Q6. Why does the Nobel committee say this discovery matters for medicine? [5 marks]

1. The committee noted that roughly a thousand human genes code for G-protein-coupled receptors, which sense signals including adrenalin, histamine, dopamine, serotonin, light, flavour and odour.
2. Because these receptors control so many physiological processes, around half of all medications in use achieve their effect by acting through them.
3. Examples mentioned include beta blockers, which work on the beta-adrenergic receptor and are widely used for heart and blood pressure conditions, and antihistamines.
4. Knowing the precise three-dimensional shape of an activated receptor, as revealed by Kobilka's 2011 image, gives researchers a much clearer target for designing new, more specific drugs.

Q7. What share of the prize did each laureate receive, and when was the prize announced? [2 marks]

1. Robert J. Lefkowitz and Brian Kobilka each received one half of the prize, which was announced on 10 October 2012.

Q8. Discuss how the work of Lefkowitz and Kobilka changed scientific understanding of how cells sense their environment. [6 marks]

1. Before their work, scientists suspected cells had some kind of receptor for hormones, based on how substances like adrenalin changed heart rate and blood pressure, but the receptors themselves had never been physically identified.
2. Lefkowitz's radioactive labelling method, begun in 1968, was the first to prove that a specific, trackable receptor molecule existed and responded measurably to a hormone.
3. Kobilka's isolation of the receptor's gene in the 1980s revealed its seven-helix structure, directly comparable to the light receptor rhodopsin in the eye.
4. This comparison led to the recognition of G-protein-coupled receptors as one large family sharing a common structural framework, rather than isolated, unrelated proteins for each separate signal.
5. Kobilka's 2011 crystal structure then showed, at the atomic level, exactly how the receptor changes shape when activated, opening a site for the G-protein to bind.
6. Together, this body of work moved the field from a vague theoretical idea of "receptors" to a detailed molecular picture that underlies the design of roughly half of today's medications.

Key takeaways

• Lefkowitz and Kobilka shared the 2012 Nobel Prize in Chemistry for studies of G-protein-coupled receptors.
• Lefkowitz's 1968 radioactive labelling method was the first to prove a hormone receptor physically exists.
• Kobilka isolated the gene for the beta-adrenergic receptor in the 1980s, revealing its seven-helix structure.
• This structure closely matched rhodopsin, the eye's light receptor, revealing a shared receptor family.
• Around a thousand human genes code for G-protein-coupled receptors, sensing hormones, light, smell and taste.
• Kobilka's 2011 crystal structure captured the receptor at the exact moment of hormone-triggered activation.
• Roughly half of all medications in use act through G-protein-coupled receptors, including beta blockers.
• Some GPCRs signal through proteins called arrestins as well as through G-proteins.

Test yourself

What phrase did the Nobel committee use to describe Kobilka's 2011 receptor image?

The committee called it "a molecular masterpiece", the result of decades of research into the receptor's structure.

Where and when was Brian Kobilka born?

Brian Kobilka was born on 30 May 1955 in Little Falls, Minnesota, USA.

What method did Lefkowitz use in 1968 to track hormone receptors?

Lefkowitz attached a radioactive iodine isotope to a hormone and used the emitted radiation to trace where it bound on cells.

What unexpected similarity did Kobilka find when he analysed the adrenergic receptor gene?

He found the receptor had seven helices crossing the membrane, the same structure as rhodopsin, the eye's light-sensing receptor.

Roughly how many human genes code for G-protein-coupled receptors?

Around a thousand human genes code for G-protein-coupled receptors.

What technique did Kobilka's team use to image the activated receptor?

They used X-ray crystallography, which works out a molecule's shape from how X-rays scatter off a crystal of it.

Name one type of drug mentioned that works through a G-protein-coupled receptor.

Beta blockers act on the beta-adrenergic receptor and are commonly used for heart and blood pressure conditions.

What affiliation did Lefkowitz hold at Duke University?

Robert J. Lefkowitz was affiliated with Duke University Medical Center in Durham, NC, USA, alongside the Howard Hughes Medical Institute.