About

Robert J. Lefkowitz is a Duke Health Distinguished Professor of Medicine, as well as a Professor of Medicine, Biochemistry, Pathology, and Chemistry at Duke University. He is a member of the Duke Cancer Institute and an associate of the Duke Initiative for Science & Society. His research focuses on biochemistry and medicine, contributing to the understanding of receptor biology and signaling pathways. Lefkowitz is affiliated with the Duke Department of Biochemistry and conducts his research at the 467 Clinical & Research Labs in Durham, North Carolina.

Research topics

• Biology
• Cell biology
• Biochemistry
• Chemistry
• Computational biology
• Pharmacology
• Internal medicine
• Bioinformatics
• Biotechnology
• Immunology
• Medicine
• Genetics
• Biophysics

Selected publications

• A positive allosteric modulator of the β1AR with antagonist activity for catecholaminergic polymorphic ventricular tachycardia

  Journal of Clinical Investigation · 2025-10-16 · 1 citations

  articleOpen access

  Orthosteric beta blockers represent the leading pharmacological intervention for managing heart diseases owing to their ability to competitively antagonize β-adrenergic receptors (βARs). However, their use is often limited by adverse effects such as fatigue, hypotension, and reduced exercise capacity, due in part to nonselective inhibition of multiple βAR subtypes. These challenges are particularly problematic in treating catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease characterized by lethal tachyarrhythmias directly triggered by cardiac β1AR activation. To identify small-molecule allosteric modulators of the β1AR with enhanced subtype specificity and robust functional antagonism of β1AR-mediated signaling, we conducted a DNA-encoded small-molecule library screen and discovered Compound 11 (C11). C11 selectively potentiates the binding affinity of orthosteric agonists to the β1AR while potently inhibiting downstream signaling after β1AR activation. C11 prevents agonist-induced spontaneous contractile activity, Ca2+ release events, and exercise-induced ventricular tachycardia in the CSQ2-/- murine model of CPVT. Our studies demonstrate that C11 belongs to an emerging class of allosteric modulators termed positive allosteric modulator antagonists that positively modulate agonist binding but block downstream function. Its pharmacological properties and selective functional antagonism of β1AR-mediated signaling make C11 a promising therapeutic candidate for the treatment of CPVT and other forms of cardiac disease associated with excessive β1AR activation.

  PublisherOA PDFDOI

• Structure and dynamics determine G protein coupling specificity at a class A GPCR

  Science Advances · 2025-03-19 · 33 citations

  articleOpen access

  G protein–coupled receptors (GPCRs) exhibit varying degrees of selectivity for different G protein isoforms. Despite the abundant structures of GPCR–G protein complexes, little is known about the mechanism of G protein coupling specificity. The β 2 -adrenergic receptor is an example of GPCR with high selectivity for Gαs, the stimulatory G protein for adenylyl cyclase, and much weaker for the Gαi family of G proteins inhibiting adenylyl cyclase. By developing a Gαi-biased agonist (LM189), we provide structural and biophysical evidence supporting that distinct conformations at ICL2 and TM6 are required for coupling of the different G protein subtypes Gαs and Gαi. These results deepen our understanding of G protein specificity and bias and can accelerate the design of ligands that select for preferred signaling pathways.

  PublisherDOI

• Mechanism of beta-arrestin 1 mediated Src activation via Src SH3 domain revealed by cryo-electron microscopy

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-07-31 · 4 citations

  preprintOpen accessSenior authorCorresponding

  Beta-arrestins (βarrs) are key regulators and transducers of G-protein coupled receptor signaling; however, little is known of how βarrs communicate with their downstream effectors. Here, we report the first structural insights into the fundamental mechanisms driving βarr-mediated signal transduction. Using cryo-electron microscopy, we elucidate how βarr1 recruits and activates the non-receptor tyrosine kinase Src, the first identified signaling partner of βarrs. βarr1 engages Src SH3 through two distinct sites, each employing a different recognition mechanism: a polyproline motif in the N-domain and a non-proline-based interaction in the central crest region. At both sites βarr1 interacts with the aromatic surface of SH3, disrupting the autoinhibited conformation of Src and directly triggering its allosteric activation. This structural evidence establishes βarr1 as an active regulatory protein rather than a passive scaffold and suggests a potentially general mechanism for βarr-mediated signaling across diverse effectors.

  PublisherOA PDFDOI

• Structure and dynamics determine G protein coupling specificity at a class A GPCR

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-03-29 · 7 citations

  preprintOpen access

  G protein coupled receptors (GPCRs) exhibit varying degrees of selectivity for different G protein isoforms. Despite the abundant structures of GPCR-G protein complexes, little is known about the mechanism of G protein coupling specificity. The β2-adrenergic receptor is an example of GPCR with high selectivity for Gαs, the stimulatory G protein for adenylyl cyclase, and much weaker for the Gαi family of G proteins inhibiting adenylyl cyclase. By developing a new Gαi-biased agonist (LM189), we provide structural and biophysical evidence supporting that distinct conformations at ICL2 and TM6 are required for coupling of the different G protein subtypes Gαs and Gαi. These results deepen our understanding of G protein specificity and bias and can accelerate the design of ligands that select for preferred signaling pathways.

  PublisherOA PDFDOI

• G Protein-Coupled Receptors: A Century of Research and Discovery

  Circulation Research · 2024-06-20 · 144 citations

  reviewOpen access

  GPCRs (G protein-coupled receptors), also known as 7 transmembrane domain receptors, are the largest receptor family in the human genome, with ≈800 members. GPCRs regulate nearly every aspect of human physiology and disease, thus serving as important drug targets in cardiovascular disease. Sharing a conserved structure comprised of 7 transmembrane α-helices, GPCRs couple to heterotrimeric G-proteins, GPCR kinases, and β-arrestins, promoting downstream signaling through second messengers and other intracellular signaling pathways. GPCR drug development has led to important cardiovascular therapies, such as antagonists of β-adrenergic and angiotensin II receptors for heart failure and hypertension, and agonists of the glucagon-like peptide-1 receptor for reducing adverse cardiovascular events and other emerging indications. There continues to be a major interest in GPCR drug development in cardiovascular and cardiometabolic disease, driven by advances in GPCR mechanistic studies and structure-based drug design. This review recounts the rich history of GPCR research, including the current state of clinically used GPCR drugs, and highlights newly discovered aspects of GPCR biology and promising directions for future investigation. As additional mechanisms for regulating GPCR signaling are uncovered, new strategies for targeting these ubiquitous receptors hold tremendous promise for the field of cardiovascular medicine.

  PublisherOA PDFDOI

• G protein–coupled receptors: from radioligand binding to cellular signaling

  Journal of Clinical Investigation · 2024-02-29 · 9 citations

  articleOpen accessSenior author

  Radioligand binding techniques facilitated the identification and study of G-protein coupled receptors that now represent the largest class of targets for therapeutic drugs.

  PublisherDOI

• Reflections from Nobel laureates in chemistry

  Cell chemical biology · 2024-08-01

  article
  PublisherDOI

• Small-molecule modulation of β-arrestins

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-12-27 · 3 citations

  preprintOpen accessSenior authorCorresponding

  β-arrestins are multifunctional regulators of G protein-coupled receptor (GPCR) signaling, orchestrating diverse downstream signaling events and physiological responses across the vast GPCR superfamily. While GPCR pharmacology has advanced to target orthosteric and allosteric sites, as well as G proteins and GRKs, comparable chemical tools to study β-arrestins remain lacking. Here, we report the discovery of small-molecule inhibitors that selectively target β-arrestins and delineate their mechanism of action through integrated pharmacological, biochemical, biophysical, and structural analyses. These inhibitors disrupt β-arrestin-engagement with agonist-activated GPCRs, impairing desensitization, internalization, and β-arrestin-dependent functions while sparing G protein-receptor coupling. Cryo-EM, MD simulations, and structure-guided mutagenesis reveal that one modulator, Cmpd-5, engages a cryptic pocket formed by the middle, C-, and lariat loops of β-arrestin1-a critical receptor-binding interface-stabilizing a distinct conformation incompatible with GPCR engagement. Together, these findings provide a mechanistic framework for β-arrestin modulation, introducing transducer-targeted strategies to fine-tune GPCR signaling and guide the development of pathway-specific therapeutics.

  PublisherOA PDFDOI

• Supplementary Data from A Phase 1 Dose-Escalation Study of Irinotecan in Combination with 17-Allylamino-17-Demethoxygeldanamycin in Patients with Solid Tumors

  2023-03-31

  preprintOpen access

  Supplementary Data from A Phase 1 Dose-Escalation Study of Irinotecan in Combination with 17-Allylamino-17-Demethoxygeldanamycin in Patients with Solid Tumors

  PublisherOA PDFDOI

• Supplementary Data from A Phase 1 Dose-Escalation Study of Irinotecan in Combination with 17-Allylamino-17-Demethoxygeldanamycin in Patients with Solid Tumors

  2023-03-31

  preprintOpen access

  Supplementary Data from A Phase 1 Dose-Escalation Study of Irinotecan in Combination with 17-Allylamino-17-Demethoxygeldanamycin in Patients with Solid Tumors

  PublisherDOI

Recent grants

• Molecular Regulation of Cardiovascular 7 TM Receptors

  NIH · $15.2M · 1976–2027

• NIH Grant R01HL070631

  NIH · $3.5M · 2012

• NIH Grant R37HL016037

  NIH · $2.5M · 1996

Frequent coauthors

• Marc G. Caron

  Duke University Hospital

  1396 shared

• Walter J. Koch

  Temple University

  446 shared

• Seungkirl Ahn

  Duke University Hospital

  367 shared

• Louis M. Luttrell

  Medical University of South Carolina

  322 shared

• Brian K. Kobilka

  Stanford University

  273 shared

• Howard A. Rockman

  Duke Medical Center

  260 shared

• Sudha K. Shenoy

  Duke University Health System

  231 shared

• Richard T. Premont

  Case Western Reserve University

  225 shared

Labs

• Lefkowitz LabPI

Education

• B.S., Chemistry

  University of Maryland

  1963

• M.D., Medicine

  Johns Hopkins University School of Medicine

  1967