Robert J. Lefkowitz, MD

Professor of Medicine
James B. Duke Distinguished Professor of Medicine
Professor of Biochemistry
Professor of Pathology
Professor of Chemistry
Member of the Duke Cancer Institute
Campus mail 467 Clin & Res Labs, Durham, NC 27710
Phone (919) 684-2974
Email address lefko001@receptor-biol.duke.edu

Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his early career as a cardiologist and his transition to biochemistry, which led to his Nobel Prize win.

Robert J. Lefkowitz, M.D. is James B. Duke Professor of Medicine and Professor of Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator of the Howard Hughes Medical Institute since 1976. Dr. Lefkowitz began his research career in the late 1960’s and early 1970’s when there was not a clear consensus that specific receptors for drugs and hormones even existed. His group spent 15 difficult years developing techniques for labeling the receptors with radioactive drugs and then purifying the four different receptors that were known and thought to exist for adrenaline, so called adrenergic receptors. In 1986 Dr. Lefkowitz transformed the understanding of what had by then become known as G protein coupled receptors because of the way the receptor signal for the inside of a cell through G proteins, when he and his colleagues cloned the gene for the beta2-adrenergic receptor. They immediately recognized the similarity to a molecule called rhodopsin which is essentially a light receptor in the retina. This unexpected finding established the beta receptor and rhodopsin as the first member of a new family of proteins. Because each has a peptide structure, which weaves across the cell membrane seven times, these receptors are referred to as seven transmembrane receptors. This super family is now known to be the largest, most diverse and most therapeutically accessible of all the different kinds of cellular receptors. There are almost a thousand members of this receptor family and they regulate virtually all known physiological processes in humans. They include the receptors not only to numerous hormones and neurotransmitters but for the receptors which mediate the senses of sweet and bitter taste and smell amongst many others. Dr. Lefkowitz also discovered the mechanism by which receptor signaling is turned off, a process known as desensitization. Dr. Lefkowitz work was performed at the most fundamental and basic end of the research spectrum and has had remarkable consequences for clinical medicine. Today, more than half of all prescription drug sales are of drugs that target either directly or indirectly the receptors discovered by Dr. Lefkowitz and his trainees. These include amongst many others beta blockers, angiotensin receptor blockers or ARBs and antihistamines. Over the past decade he has discovered novel mechanisms by which the receptors function which may lead to the development of an entirely new class of drugs called “biased agonists”. Several such compounds are already in advanced stages of clinical testing. Dr. Lefkowitz has received numerous honors and awards, including the National Medal of Science, the Shaw Prize, the Albany Prize, and the 2012 Nobel Prize in Chemistry. He was elected to the USA National Academy of Sciences in 1988, the Institute of Medicine in 1994, and the American Academy of Arts and Sciences in 1988.

Education and Training

  • Resident, Medicine, Massachusetts General Hospital, 1970 - 1971
  • Resident, Medicine, Columbia University, 1967 - 1968
  • Intern, Medicine, Columbia University, 1966 - 1967
  • M.D., Columbia University, 1966

Publications

Smith, J. S., L. Nicholson, J. Suwanpradid, R. Glenn, J. Gundry, P. Alagesan, N. Knape, et al. “678 Biased CXCR3 ligands differentially alter allergic contact hypersensitivity and chemotaxis.” In Journal of Investigative Dermatology, 137:S117–S117. Elsevier BV, 2017. https://doi.org/10.1016/j.jid.2017.02.701.

Full Text

Stoppel, Laura J., Benjamin D. Auerbach, Rebecca K. Senter, Anthony R. Preza, Robert J. Lefkowitz, and Mark F. Bear. “β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X.” Cell Rep 18, no. 12 (March 21, 2017): 2807–14. https://doi.org/10.1016/j.celrep.2017.02.075.

PMID
28329674
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Cahill, Thomas J., Alex R. B. Thomsen, Jeffrey T. Tarrasch, Bianca Plouffe, Anthony H. Nguyen, Fan Yang, Li-Yin Huang, et al. “Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis.” Proc Natl Acad Sci U S A 114, no. 10 (March 7, 2017): 2562–67. https://doi.org/10.1073/pnas.1701529114.

PMID
28223524
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Ahn, Seungkirl, Alem W. Kahsai, Biswaranjan Pani, Qin-Ting Wang, Shuai Zhao, Alissa L. Wall, Ryan T. Strachan, et al. “Allosteric "beta-blocker" isolated from a DNA-encoded small molecule library.” Proc Natl Acad Sci U S A 114, no. 7 (February 14, 2017): 1708–13. https://doi.org/10.1073/pnas.1620645114.

PMID
28130548
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Kahsai, Alem W., James W. Wisler, Jungmin Lee, Seungkirl Ahn, Thomas J. Cahill Iii, S Moses Dennison, Dean P. Staus, et al. “Conformationally selective RNA aptamers allosterically modulate the β2-adrenoceptor.” Nat Chem Biol 12, no. 9 (September 2016): 709–16. https://doi.org/10.1038/nchembio.2126.

PMID
27398998
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Thomsen, Alex R. B., Bianca Plouffe, Thomas J. Cahill, Arun K. Shukla, Jeffrey T. Tarrasch, Annie M. Dosey, Alem W. Kahsai, et al. “GPCR-G Protein-β-Arrestin Super-Complex Mediates Sustained G Protein Signaling.” Cell 166, no. 4 (August 11, 2016): 907–19. https://doi.org/10.1016/j.cell.2016.07.004.

PMID
27499021
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Staus, Dean P., Ryan T. Strachan, Aashish Manglik, Biswaranjan Pani, Alem W. Kahsai, Tae Hun Kim, Laura M. Wingler, et al. “Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation.” Nature 535, no. 7612 (July 21, 2016): 448–52. https://doi.org/10.1038/nature18636.

PMID
27409812
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Rein, Lindsay A. M., James W. Wisler, Barbara S. Theriot, Li-Yin Huang, Richard T. Premont, and Robert J. Lefkowitz. “beta-arrestin2 Is Necessary for Development of MPLW515L Mutant Primary Myelofibrosis.” In Blood, Vol. 126. AMER SOC HEMATOLOGY, 2015.

Scholars@Duke

Wisler, James W., Emily M. Harris, Michael Raisch, Lan Mao, Jihee Kim, Howard A. Rockman, and Robert J. Lefkowitz. “The role of β-arrestin2-dependent signaling in thoracic aortic aneurysm formation in a murine model of Marfan syndrome.” Am J Physiol Heart Circ Physiol 309, no. 9 (November 2015): H1516–27. https://doi.org/10.1152/ajpheart.00291.2015.

PMID
26371162
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