2010 Smissman Memorial Lecturer
Brian K. Kobilka, MD (Web Page)
- Chair, Department of Molecular and Cellular Physiology and Medicine Stanford University
Public Lecture and Award Presentation
- G Protein Coupled Receptors – Complex Behavior and Challenges for Discovering Novel Drugs
- Crystal Structures of the β2-Adrenoceptor: How We Got There and What We Learned
- Features of GPCR Activation: Insights from Fluorescence and NMR Spectroscopy
Dr. 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 1990 he joined the faculty of Medicine and Molecular and Cellular Physiology at Stanford University. He was promoted to Professor of Medicine and Molecular and Cellular Physiology in 2000.
Dr. Kobilka's research interest has been the structure and mechanism of action of G protein–coupled receptors, with a focus on adrenergic receptors as model systems. G protein–coupled receptors (GPCRs) are the largest family of receptors for hormones and neurotransmitters in the human genome. Dr. Kobilka’s contributions in this field began during his postdoctoral fellowship with isolating the gene for the β2-adrenergic receptor (β2AR), the first GPCR for a hormone or neurotransmitter to be cloned, as well as genes for four other adrenergic receptors and a serotonin receptor. His group at Stanford was one of the first to apply gene disruption technology to investigate GPCR physiology. They disrupted the genes for 5 of the 9 adrenergic receptor subtypes in mice. Characterization of these mice led to the identification of specific roles for these receptors in cardiovascular, metabolic and behavioral physiology.
Dr. Kobilka was one of the first investigators to develop methods for high-level production of recombinant GPCR protein, and apply state of the art spectroscopic techniques to study ligand-induced conformational changes in the β2AR. These studies provided the first direct evidence for ligand-specific conformational states, and showed that agonist activation of the β2AR occurs through at least two kinetically distinguishable conformational states. Applying these spectroscopic tools to characterize interactions between receptors and G proteins demonstrated how different classes of ligands influence the physical coupling of these proteins, and showed that β2ARs are functional as monomers, and that dimerization is not required for G protein activation.
Dr. Kobilka’s group was the first to obtain a high-resolution crystal structure of a GPCR activated by diffusible ligands. Guided by insights from their earlier biochemical and biophysical studies on the β2AR, they took two different approaches to enhance receptor stability and facilitate crystallogenesis. The first approach involved the development of a conformationally sensitive antibody fragment (Fab) that recognized and stabilized a dynamic interface between two transmembrane domains (TM5 and TM6). They were able to obtain crystals of the β2AR–Fab complex, resulting in a 3.4Å structure. Their second approach used protein engineering to design a more stable and crystallizable receptor resulting in a 2.4Å structure of the β2AR. These were the first high-resolution structures for a GPCR activated by a diffusible hormone or neurotransmitter. Comparison of β2AR and rhodopsin provided structural insights into functional similarities and differences between these two receptors. Moreover, the β2AR structure provided a more relevant template for homology models of closely related monoamine receptors that could have an impact on drug discovery for these clinically important GPCRs. Finally, the protein engineering strategy developed for the β2AR has been successfully applied to obtain crystal structures of other GPCRs.
Dr. Kobilka’s academic awards and honors include: 1994 John Jacob Abel Award (American Society for Pharmacology and Experimental Therapeutics); 2004 Javits Investigator Award from the NINDS; 2006 Doisy Lectureship (University of Illinois at Urbana–Champaign); 2010 Julius Axelrod Award (American Society for Pharmacology and Experimental Therapeutics); and the 2010 Krebs Lectureship (University of Washington).