Robert Lefkowitz

Overview:

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.

Positions:

The Chancellor's Distinguished Professor of Medicine

Medicine, Cardiology
School of Medicine

Professor of Medicine

Medicine, Cardiology
School of Medicine

Professor of Biochemistry

Biochemistry
School of Medicine

Professor of Pathology

Pathology
School of Medicine

Professor of Chemistry

Chemistry
Trinity College of Arts & Sciences

Associate of the Duke Initiative for Science & Society

Duke Science & Society
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1966

Columbia University

Intern, Medicine

Columbia University

Resident, Medicine

Columbia University

Resident, Medicine

Massachusetts General Hospital

Publications:

HISTORICAL PERSPECTIVE: From Receptors to G Proteincoupled Receptors to Seven Transmembrane Receptors: A Journey of Discovery

MLA Citation
Lefkowitz, Robert, editor. HISTORICAL PERSPECTIVE: From Receptors to G Proteincoupled Receptors to Seven Transmembrane Receptors: A Journey of Discovery. Royal Society of Chemistry, 2011, pp. P021–35. Crossref, doi:10.1039/9781849733441-fp021.
URI
https://scholars.duke.edu/individual/pub1547828
Source
crossref
Published Date
Start Page
P021
End Page
P035
DOI
10.1039/9781849733441-fp021

Historical Background and Introduction

Authors
Bond, RA; Lefkowitz, RJ
MLA Citation
Bond, Richard A., and Robert J. Lefkowitz. “Historical Background and Introduction.” G PROTEIN-COUPLED RECEPTORS AS DRUG TARGETS: ANALYSIS OF ACTIVATION AND CONSTITUTIVE ACTIVITY, vol. 24, 2005, pp. 3–10.
URI
https://scholars.duke.edu/individual/pub1547829
Source
wos-lite
Volume
24
Published Date
Start Page
3
End Page
10

Unique Positive Cooperativity Between the beta-Arrestin-Biased beta-Blocker Carvedilol and a Small Molecule Positive Allosteric Modulator of the beta 2-Adrenergic Receptor (vol 100, pg 513, 2021)

Authors
Pani, B; Ahn, S; Rambarfat, PK; Vege, S; Kahsai, AW; Liu, A; Valan, BN; Status, DP; Costa, T; Lefkowitz, RJ
URI
https://scholars.duke.edu/individual/pub1510813
Source
wos-lite
Published In
Molecular Pharmacology
Volume
100
Published Date
Start Page
597
End Page
597

Marc G. Caron (1946-2022).

Authors
Lefkowitz, RJ; Amara, SG
MLA Citation
Lefkowitz, Robert J., and Susan G. Amara. “Marc G. Caron (1946-2022).Nat Neurosci, vol. 25, no. 9, Sept. 2022, p. 1120. Pubmed, doi:10.1038/s41593-022-01145-y.
URI
https://scholars.duke.edu/individual/pub1532258
PMID
35915165
Source
pubmed
Published In
Nat Neurosci
Volume
25
Published Date
Start Page
1120
DOI
10.1038/s41593-022-01145-y

GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision.

β-arrestins bind G protein-coupled receptors to terminate G protein signaling and to facilitate other downstream signaling pathways. Using single-molecule fluorescence resonance energy transfer imaging, we show that β-arrestin is strongly autoinhibited in its basal state. Its engagement with a phosphopeptide mimicking phosphorylated receptor tail efficiently releases the β-arrestin tail from its N domain to assume distinct conformations. Unexpectedly, we find that β-arrestin binding to phosphorylated receptor, with a phosphorylation barcode identical to the isolated phosphopeptide, is highly inefficient and that agonist-promoted receptor activation is required for β-arrestin activation, consistent with the release of a sequestered receptor C tail. These findings, together with focused cellular investigations, reveal that agonism and receptor C-tail release are specific determinants of the rate and efficiency of β-arrestin activation by phosphorylated receptor. We infer that receptor phosphorylation patterns, in combination with receptor agonism, synergistically establish the strength and specificity with which diverse, downstream β-arrestin-mediated events are directed.
Authors
Asher, WB; Terry, DS; Gregorio, GGA; Kahsai, AW; Borgia, A; Xie, B; Modak, A; Zhu, Y; Jang, W; Govindaraju, A; Huang, L-Y; Inoue, A; Lambert, NA; Gurevich, VV; Shi, L; Lefkowitz, RJ; Blanchard, SC; Javitch, JA
MLA Citation
Asher, Wesley B., et al. “GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision.Cell, vol. 185, no. 10, May 2022, pp. 1661-1675.e16. Pubmed, doi:10.1016/j.cell.2022.03.042.
URI
https://scholars.duke.edu/individual/pub1519459
PMID
35483373
Source
pubmed
Published In
Cell
Volume
185
Published Date
Start Page
1661
End Page
1675.e16
DOI
10.1016/j.cell.2022.03.042