Speaker Bio

Brian Kobilka, MD

Professor, Department of Molecular and Cellular Physiology
Hélène Irwin Fagan Chair in Cardiology
Stanford University

Brian Kobilka received Bachelor of Science Degrees in Biology and Chemistry from the University of Minnesota, Duluth in 1977. He graduated from Yale University School of Medicine in 1981 and completed residency training in Internal Medicine at the Barnes Hospital, Washington University School of Medicine, St. Louis, Missouri in 1984. From 1984-1989 he was a postdoctoral fellow in the laboratory of Robert Lefkowitz at Duke University. In 1989 he joined the faculty of Medicine and Molecular and Cellular Physiology at Stanford University. Research in the Kobilka lab focuses on the structure and mechanism of action of G-protein-coupled receptors (GPCRs). GPCRs comprise the largest family of receptors for hormones and neurotransmitters in the human genome. The Kobilka lab applies a spectrum of biochemical, biophysical and structural approaches to understand GPCR signaling at the molecular level. Dr. Kobilka is a member of the National Academy of Sciences, the National Academy of Medicine, and the American Academy of Arts and Sciences. In 2012, Brian Kobilka was awarded the Nobel Prize in Chemistry, along with Robert Lefkowitz, for his work in determining the structure of a GPCR in inactive and G protein-coupled states.

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Abstract

G Protein Coupled Receptors: Challenges and New Approaches to Drug Discovery

Brian Kobilka,
Department of Molecular and Cellular Physiology, Stanford University

G protein-coupled receptors (GPCRs) mediate the majority of cellular responses to hormones and neurotransmitters, as well as the senses of sight, smell and taste. They represent the largest class of drug targets for the pharmaceutical industry; however, there are many obstacles to the discovery and development of safe and effective drugs for specific GPCR targets. I will provide an overview of the molecular basis of GPCR signaling, and discuss the challenges in drug discovery for GPCRs using the µ-opioid receptor (µOR) as a model system. The management of acute and chronic pain is one of the greatest challenges in modern medicine. While effective, many of the currently used opioid analgesics are highly addictive and their increased clinical use over the past 20 years is partially responsible for the opioid epidemic. The properties of more recently discovered µOR agonists suggest that it may be possible to separate analgesia from liabilities including addiction, tolerance and respiratory suppression. The µOR can signal through six G protein isoforms (Gi1,2,3, GoA,B, Gz), and through arrestin 2 and 3. We have observed that different µOR agonists differentially activate these signaling pathways. I will discuss what we have learned about the structural basis for G protein isoform and arrestin-biased signaling by the µOR.