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Robert Lefkowitz and Brian Kobilka were awarded the prize for groundbreaking discoveries that reveal the inner workings of an important family of cell receptors, G-protein–coupled receptors, that enable cells to sense their environment.
Dr Bernadette Byrne, Reader in Molecular Membrane Biology at Imperial College London, said:
“It is impossible to overstate the importance of the collective body of research from both Prof RJ Lefkowitz and Prof Brian Kobilka on the structure and function of the G-protein coupled receptors. These essential proteins sit within the fatty layer surrounding cells and have key roles in controlling a vast number of cellular processes including immune responses, heart function and metabolism. Lefkowitz and Kobilka, have more than any other researchers, meticulously investigated how these proteins work at an incredibly detailed level. Their findings have shone a light onto the staggeringly complex world of how hormones, neurotransmitters and drugs control cellular function and opened the door to the development of new therapeutics with potential to treat a vast array of diseases.”
Prof Humphrey Rang, President-Elect of the British Pharmacological Society, said:
“The British Pharmacological Society welcomes the Nobel Prize committee’s recognition of the work of Robert Lefkowitz and Brian Kobilka on the structure and function of G-protein coupled receptors (GPCRs). This type of receptor is of major importance to pharmacology and the target of many valuable drugs developed in recent years. The discoveries of Lefkowitz and Kobilka have contributed much to our basic understanding of the function of these ubiquitous receptors and their role in both health and disease.
“We are proud of British pharmacologists’ contributions to our understanding of GPCRs, which were accomplished in parallel with the work of Lefkowitz and Kobilka. Significant research needs to continue in order to identify further opportunities for improving patients’ health and wellbeing.”
Dr Richard Henderson, MRC Laboratory of Molecular Biology, University of Cambridge, said:
“This is a thoroughly deserved Nobel Prize award that will be welcomed throughout the scientific community.
“Lefkowitz was one of the very first pioneers who started to tackle the nature of hormone activation in cells using radiolabelled ligands in the 1960s and 1970s to characterise the receptor structures and begin biochemical work. He had a medical training and is considered to be the father of the field. Apart from great work from his own laboratory, he has trained as students or postdocs many of the people now prominent in the field, inlcuding Brian Kobilka.
“Kobilka joined Lefkowitz’ laboratory as a postdoc in the 1980s and was the very first to identify, clone and sequence the gene for human beta-2 adrenergic receptor. To everyone’s surprise, it turned out to have strong homology to the visual pigment in the eye, rhodopsin. In particular both molecules were made up of 7 trans-membrane alpha-helical segments of the polypeptide, as had been found first in the bacteriorhodopsin, a distantly related membrane protein. They were also both found to carry out their signalling function via activation of the trimeric cytoplasmic G-protein complex, hence the family name was coined of G-protein coupled receptors (GPCRs). A flood of related genes were identified during the later part of the 1980s and early 1990s using a range of cloning strategies. Finally, once the human genome sequence was determined in 1999-2000, it became clear that this GPCR family is one of the largest and most important that govern human physiology. There are now more than 350 identified GPCRs and more than 400 olfactory (smell) GPCRS in the human genome, so probably amounting to about 4% of the proteins in man.
“During the early part of the 21st century Kobilka turned his attention to trying to obtain three-dimensional structures of members of the GPCR family and was once again first with the X-ray crystal structure of the human beta-2 adrenergic receptor published in 2007. The visual pigment rhodopsin had its structure determined in 2000 but the beta-adrenergic receptor was the very first that was hormone-activated. Finally in February 2012 Kobilka, in collaboration with Roger Tsunahara, managed to crystallise and solve the structure of the complete beta-adrenergic receptor in its activated state in complex with the trimeric G-protein complex.
“In summary, Kobilka led the work that produced the first gene sequence, the first 3D structure and the first structure of a fully activated G-protein complex. This was a 30 year effort, during which he had early HHMI (Howard Hughes Medical Institute) support but lost it over 10 years ago. Nevertheless, with NIH funding, he persisted with many, many novel approaches until all the problems were solved and the beautiful picture of how this fascinating signalling system works was revealed in full molecular detail. Everyone agrees that Kobilka has done more than anyone else to make the practical and conceptual jumps that have opened up this field. There are now 14 or 15 published GPCR structures, several from Kobilka’s laboratory, and new drugs are being designed using the new knowledge of GPCR structure and function that will eventually improve medical treatments.”
Prof Anthony Watts, Oxford University and managing editor of the European Biophysical Journal, says of Brian Kobilka:
“This prize could not go to a nicer, polite and considerate man, and it is a pleasure to know him.
“Brian’s perseverance of many years of working on a major class of neuroreceptors has paid off. He has spectacularly obtained the atomic details of several of these receptors, and more importantly, focussed on using a range of sophisticated biophysical and biochemical methods to help us understand how they function. Since this family of proteins is the target for a majority of current drugs, Brian’s contribution is unsurpassed in helping our understanding about their involvement in disease.
“The Nobel Prize could not go to a nicer person.”
Prof David Phillips, Immediate Past-President of the Royal Society of Chemistry, said:
“It’s very interesting to see that both the 2012 Nobel Prizes for Chemistry and Medicine have been awarded to cell biologists. This shows what an important role chemistry has to play in cell biology studies.
“G-protein-coupled receptors are ubiquitous in the function of cells in the body and help us to sense light, flavour and odour. They are also responsible for the human body’s reactions to chemicals in the body such as adrenaline, histamine, dopamine and serotonin – which are associated with medical conditions such as allergies, depression and Parkinson’s disease.
“But before Robert Lefkowitz identified them and, together with Brian Kobilka determined how they work, nobody even knew they existed.
“The key to understanding this family of proteins has been the determination of their molecular structure.
“Now, half of all medications achieve their effect through G-protein-coupled receptors. It is no surprise that Lefkowitz and Kobilka have been awarded this year’s Nobel Prize because these receptors have such a vital implication for human health.”
Martyn Poliakoff, Foreign Secretary and Vice-President of the Royal Society, said:
“The work of Robert Lefkowitz and Brian Kobilka has helped us to understand more fully how our cells react to external influences such as the hormone adrenalin. Understanding how our bodies prepare for fight or flight is just one of the applications of their work which has also opened the door for a wide range of new, more effective drug treatments with fewer side effects. Indeed as many as 50% of pharmaceutical drugs operate via the receptors for such hormones.
“The practical benefits of Kobilka and Lefkowitz work highlight just how exciting and important chemistry is. I hope that there are even more young people across the world who will be inspired to become chemists when they hear about the prize.”
Prof Mark Sansom, David Phillips Professor of Molecular Biophysics & Head of Department of Biochemistry, University of Oxford, Said:
“G-protein coupled receptors have for a long time been the holy grail of membrane protein research. They are fundamental to regulation of many physiological processes, from the nervous system to taste and smell. They are also a major class of drug target and are incredibly important to the pharmaceutical industry. In particular Kobilka’s work in determining the structure of G-protein coupled receptors has revolutionised our understanding of how they work as small ‘molecular machines’ and will lead to enormous advances in drug design.
“Thus this is work at the biology/chemistry interface of great importance, and also with considerable impact in the broader sense.”
Dr Mark Downs, Chief Executive, Society of Biology, said:
“The critical role receptors play in biological function is now taken for granted. This ground breaking work spanning genetics and biochemistry has laid the basis for much of our understanding of modern pharmacology as well as how cells in different parts of living organisms can react differently to external stimulation such as light and smell or the internal systems which control our bodies such as hormones.”