Nobel Prize in Chemistry 2012

The Nobel Prize in Chemistry for 2012 has been awarded to Robert Lefkowitz (left), Howard Hughes Medical Institute, Duke University, USA, and Brian Kobilka (right), Stanford University, USA, for their work on G-protein-coupled receptors (GPCRs).

GPCRs are members of the family of integral membrane proteins (IMPs), which mediate the transfer of material and signals between the environment and the cytoplasm. There are about 1,000 GPCRs in the human body, all of which have similar molecular structures, defined by an amino acid sequence which crosses the plasma membrane seven times. This similarity means GPCRs can be effectively targeted and today as many as 30–50 % of all prescription drugs are designed to “fit” these structures. This has led to new anti-histamines, ulcer drugs, and beta blockers that help relieve hypertension, angina, and coronary disease.

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.

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.

Papers by Robert Lefkowitz:

G-protein receptor kinase 3 (GRK3) influences opioid analgesic tolerance but not opioid withdrawal,
Gregory W. Terman, Wenzhen Jin, Young-Pyo Cheong, Janet Lowe, Marc G. Caron, Robert J. Lefkowitz, Charles Chavkin,
Br. J. Pharmacol. 2004, 141(1), 55–64.
DOI: 10.1038/sj.bjp.0705595
Purification, crystallization and preliminary X-ray diffraction studies of a complex between G protein-coupled receptor kinase 2 and Gβ1γ2,
David T. Lodowski, Jennifer F. Barnhill, Julie A. Pitcher, W. Darrell Capel, Robert J. Lefkowitz, John J. G. Tesmer,
Acta Crystallogr., Sect. D: Biol. Crystallogr. 2003, 59(5), 936–939.
DOI: 10.1107/S0907444903002622
β2-Adrenergic receptor overexpression in the developing mouse heart: evidence for targeted modulation of ion channels,
R.-H. An, B. M. Heath, J. P. Higgins, W. J. Koch, R. J. Lefkowitz, R. S. Kass,
J. Physiol. 1999, 516(1), 19–30.
DOI: 10.1111/j.1469-7793.1999.019aa.x
Synthetic peptides of the hamster beta 2-adrenoceptor as substrates and inhibitors of the beta-adrenoceptor kinase,
J. L. Benovic, J. Onorato, M. J. Lohse, H. G. Dohlman, C. Staniszewski, M. G. Caron, R. J. Lefkowitz,
Br. J. Clin. Pharmacol. 1990, 30(S1), 3S–12S.
DOI: 10.1111/j.1365-2125.1990.tb05462.x
Cell-free Desensitization of the β-Adrenergic Receptor: Evidence that Multiple Protein Kinases Can Phosphorylate and Desensitize the Receptor,
Ponnal Nambi, Jack R. Peters, David R. Sibley, Robert J. Lefkowitz,
Ann. N. Y. Acad. Sci. 1986, 463(1), 122–124.
DOI: 10.1111/j.1749-6632.1986.tb21519.x
Identification of the Subunit Structure of Rat Pineal Adrenergic Receptors by Photoaffinity Labeling,
Kenneth E. J. Dickinson, L. M. Fredrik Leeb-Lundberg, Ruth H. Strasser, Marc G. Caron, Robert J. Lefkowitz,
J. Neurochem. 1986, 46(4), 1153–1160.
DOI: 10.1111/j.1471-4159.1986.tb00630.x
Polymeric drugs by direct copolymerization: Polymer of β-adrenergic antagonist alprenolol and its binding to receptors and antibodies,
Josef Pitha, Jordan Zjawiony, Robert J. Lefkowitz, Marc G. Caron,
Makromol. Chem. 1981, 182(7), 1945–1950.
DOI: 10.1002/macp.1981.021820707
Beta-adrenergic receptors: Regulatory role of agonists,
Robert J. Lefkowitz, Lee E. Limbird, Lewis T. Williams, Michael Wessels,
J. Supramol. Struct. 1978, 8(4), 501–510.
DOI: 10.1002/jss.400080412
Acth-Receptor Interaction in the Adrenal: A Model for the Initial Step in the Action of Hormones that Stimulate Adenyl Cyclase,
Robert J. Lefkowitz, Jesse Roth, Ira Pastan,
Ann. N. Y. Acad. Sci. 1971, 185(1), 195–209.
DOI: 10.1111/j.1749-6632.1971.tb45249.x

Book Chapters by Robert Lefkowitz:

Historical Background and Introduction,
Richard A. Bond, Robert J. Lefkowitz,
In G Protein-Coupled Receptors as Drug Targets: Analysis of Activation and Constitutive Activity, Volume 24,
Roland Seifert, Thomas Wieland (Eds.),
Wiley-VCH, Weinheim, Germany, 2005.
DOI: 10.1002/352760734X.ch1
Molecular Mechanisms of Coupling in Hormone Receptor-Adenylate Cyclase Systems,
Jeffrey M. Stadel, Andre De Lean, Robert J. Lefkowitz,
In Advances in Enzymology and Related Areas of Molecular Biology, Volume 53,
Alton Meister (Ed.),
John Wiley & Sons, New York, USA, 1982.
DOI: 10.1002/9780470122983.ch1