Nobel Prize in Chemistry 2012

The Nobel Prize in Chemistry has been awarded to Robert Lefkowitz (left) from Howard Hughes Medical Institute, Duke University, USA and Brian Kobilka (right), Stanford University, USA for their work on G-coupled protein receptors (GPCRs).

What are GPCRs ?

GPCRs are G-Protein coupled receptors, which are members of integral membrane proteins (IMPs) which transduce extracellular stimuli into intracellular signals. GPCRs are essentially both the gatekeepers and molecular messengers of the cell, transmitting signals from inside to outside. The signal can consist of an astonishing variety of stimuli, from photons (light) to neurotransmitters to hormones. They mediate virtually every important physiological process, from immune system function to taste and smell to the fight-or-flight response in humans. GPCRs are also immensely important in medicine and are the target of about 30% of all drugs. Naturally occurring small molecules which bind to GPCRs include adrenaline, prostaglandins, dopamine, somatostatin and adenosine. Drug-like small molecules which bind to GPCRs include caffeine, morphine, heroin and histamine. The range of stimuli and molecules that GPCRs respond to is remarkable and their role in the workings of life is unquestioned. So far eight different types of GPCR structures have been determined by X-ray crystallography: β2 Adrenergic Receptor, β1 Adrenergic Receptor, Adenosine Receptor, Rhodopsin, CXCR4 Chemokine receptor, Dopamine D3 receptor, the Histamine Receptor and the S1P1 Sphingosine 1-phosphate receptor.See for more details....

To Know more about GPCRs.......click here.

There are over 375 GPCRs encoded in the human genome, of which 225 have known ligands and 150 are orphan targets. GPCRs are the site of action of 25-30% of current drugs. Six of the top ten and 60 of the top 200 best-selling drugs in the US in 2010 target GPCRs, generating multi-billion dollar sales annually.

Drug discovery targeting GPCRs remains challenging, however. In contrast to classes of soluble protein drug targets, such as kinases and proteases, the understanding of GPCRs has been severely hampered by the lack of structural and mechanistic knowledge and an understanding of how compounds interact with them. This has resulted in a general lack of quality GPCR drug leads advancing through pharma pipelines, high failure rates and no successful NCEs to multiple validated high-value targets.

Robert Lefkowitz studied at Columbia College, USA, and gained his M.D. from Columbia University College of Physicians and Surgeons in 1966. He served his internship and residency at the College of Physicians and Surgeons before joining the US National Institutes of Health in1968. He completed his medical residency and research and clinical training in cardiovascular disease at the Massachusetts General Hospital, Boston, USA, from 1970–1973. In 1973 he joined the faculty at the Duke University Medical Center, USA. In 1977 he was promoted to Professor of Medicine and in 1982 to James B. Duke Professor of Medicine at Duke University. 

Lefkowitz' research focuses on the detailed characterization of the sequence, structure, and function of GPCRs, particularly the β-adrenergic and related receptors, and the two families of proteins which regulate them, the G-protein-coupled receptor kinases (GRKs) and β-arrestins. He discovered the similarity of the GPCRs' structures through first cloning the gene for the β-adrenergic receptor and later the genes for eight adrenergic receptors for adrenaline and noradrenaline.

Research Publications of Rober Lefkowitz...click here

Brian Kobilka studied biology and chemistry at the University of Minnesota, USA. He earned his M.D. from Yale University School of Medicine, USA, which was followed by a residency in internal medicine at Washington University School of Medicine, Barnes Hospital, USA. He was a postdoctoral researcher in the group of Robert Lefkowitz at Duke University, USA, where he started work on cloning the β2-adrenergic receptor. Kobilka moved to Stanford University, USA, in 1989, where he is currently Professor in the departments of Molecular and Cellular Physiology and Medicine.

Kobilka's research focuses on the structure and activity of GPCRs, in particular, determining the molecular structure of the β2-adrenergic receptor. He has developed direct methods to monitor ligand-induced conformational changes in purified β2-adrenergic receptor, and has obtained a high-resolution crystal structure of this receptor.

Research Publications of Brian Kobilka...click here