Stanford’s Brian Kobilka, M.D., delivers last week’s Discovery Lecture. (photo by Anne Rayner)
Lecturer details efforts to visualize nature’s sensors
With animated, rotating protein structures as his backdrop at last week's Discovery Lecture, Brian Kobilka, M.D., described his group's 15-year odyssey to determine the crystal structure of the beta-2 adrenergic receptor.
“I've always wanted to make slides like this,” said Kobilka, professor of Medicine and Molecular and Cellular Physiology at Stanford University, of the colored, swirling “ribbons” that showed the protein's three-dimensional structure.
This fall, his team published the beta-2 adrenergic receptor structure, the first for a human “G protein coupled receptor” (GPCR). GPCRs are nature's most versatile biological sensors, and they are targets for about half of all currently prescribed drugs.
“Nearly two decades after cloning the first G protein coupled receptors, we're still largely getting drugs for these receptors through old-fashioned trial and error methods, as opposed to structure-based drug discovery tools,” Kobilka said. “A goal in understanding how (the receptor) works at a structural level is to try to facilitate the development of more effective and more selective drugs for this whole family of proteins.”
Kobilka's group used the beta-2 adrenergic receptor — one of the sensors for the hormone adrenaline — as a model for the GPCR family. His team crystallized two modified versions of the receptor and compared their structures. The crystal structures confirmed earlier biophysical findings that suggested the receptor exists in multiple conformations.
“The receptor doesn't exist in an (empty) state that will readily bind ligand; it's not a lock-and-key model,” Kobilka said. Instead, the structural findings suggest that the ligand has to engage the receptor, “and then through a series of conformational fluctuations, (the receptor) will begin to wander … until it stabilizes the protein in an active conformation.”
“Brian has changed our thinking about how receptors work at a fundamental atomic level,” said Lee Limbird, Ph.D., vice chancellor for Research at Meharry Medical College.
The lecture honored Allan D. Bass, M.D., who served as chair of Pharmacology from 1953 to 1973, and is credited by many as the architect of Vanderbilt's emergence as an international leader in the discipline of Pharmacology.
For a complete schedule of the Discovery Lecture Series and archived video of previous lectures, go to www.mc.vanderbilt.edu/discoveryseries.