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

Suomivuori, Carl-Mikael, Naomi R. Latorraca, Laura M. Wingler, Stephan Eismann, Matthew C. King, Alissa L. W. Kleinhenz, Meredith A. Skiba, et al. “Molecular Mechanism of Biased Signaling in a Prototypical G-proteincoupled Receptor.” In Biophysical Journal, 118:162A-162A. CELL PRESS, 2020.

Scholars@Duke

Nguyen, Anthony H., Alex R. B. Thomsen, Thomas J. Cahill, Rick Huang, Li-Yin Huang, Tara Marcink, Oliver B. Clarke, et al. “Structure of an endosomal signaling GPCR-G protein-β-arrestin megacomplex.” Nat Struct Mol Biol 26, no. 12 (December 2019): 1123–31. https://doi.org/10.1038/s41594-019-0330-y.

PMID
31740855
Full Text

Staus, Dean P., Laura M. Wingler, Dmitry Pichugin, Robert Scott Prosser, and Robert J. Lefkowitz. “Detergent- and phospholipid-based reconstitution systems have differential effects on constitutive activity of G-protein-coupled receptors.” J Biol Chem 294, no. 36 (September 6, 2019): 13218–23. https://doi.org/10.1074/jbc.AC119.009848.

PMID
31362983
Full Text

Jain, Mukesh K., Vivian G. Cheung, Paul J. Utz, Brian K. Kobilka, Tadataka Yamada, and Robert Lefkowitz. “Saving the Endangered Physician-Scientist - A Plan for Accelerating Medical Breakthroughs.” N Engl J Med 381, no. 5 (August 1, 2019): 399–402. https://doi.org/10.1056/NEJMp1904482.

PMID
31365796
Full Text

Liu, Xiangyu, Ali Masoudi, Alem W. Kahsai, Li-Yin Huang, Biswaranjan Pani, Dean P. Staus, Paul J. Shim, et al. “Mechanism of β2AR regulation by an intracellular positive allosteric modulator.” Science 364, no. 6447 (June 28, 2019): 1283–87. https://doi.org/10.1126/science.aaw8981.

PMID
31249059
Full Text

Wingler, Laura M., Conor McMahon, Dean P. Staus, Robert J. Lefkowitz, and Andrew C. Kruse. “Distinctive Activation Mechanism for Angiotensin Receptor Revealed by a Synthetic Nanobody.” Cell 176, no. 3 (January 24, 2019): 479-490.e12. https://doi.org/10.1016/j.cell.2018.12.006.

PMID
30639100
Full Text

Wingler, Laura M., Matthias Elgeti, Daniel Hilger, Naomi R. Latorraca, Michael T. Lerch, Dean P. Staus, Ron O. Dror, Brian K. Kobilka, Wayne L. Hubbell, and Robert J. Lefkowitz. “Angiotensin Analogs with Divergent Bias Stabilize Distinct Receptor Conformations.” Cell 176, no. 3 (January 24, 2019): 468-478.e11. https://doi.org/10.1016/j.cell.2018.12.005.

PMID
30639099
Full Text

Kim, Jihee, Chad A. Grotegut, James W. Wisler, Tianyu Li, Lan Mao, Minyong Chen, Wei Chen, Paul B. Rosenberg, Howard A. Rockman, and Robert J. Lefkowitz. “β-arrestin 1 regulates β2-adrenergic receptor-mediated skeletal muscle hypertrophy and contractility.” Skelet Muscle 8, no. 1 (December 27, 2018): 39. https://doi.org/10.1186/s13395-018-0184-8.

PMID
30591079
Full Text

Luttrell, Louis M., Jialu Wang, Bianca Plouffe, Jeffrey S. Smith, Lama Yamani, Suneet Kaur, Pierre-Yves Jean-Charles, et al. “Manifold roles of β-arrestins in GPCR signaling elucidated with siRNA and CRISPR/Cas9.” Sci Signal 11, no. 549 (September 25, 2018). https://doi.org/10.1126/scisignal.aat7650.

PMID
30254056
Full Text

Choi, Minjung, Dean P. Staus, Laura M. Wingler, Seungkirl Ahn, Biswaranjan Pani, William D. Capel, and Robert J. Lefkowitz. “G protein-coupled receptor kinases (GRKs) orchestrate biased agonism at the β2-adrenergic receptor.” Sci Signal 11, no. 544 (August 21, 2018). https://doi.org/10.1126/scisignal.aar7084.

PMID
30131371
Full Text

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