Structural insights into the dynamic process of G protein coupled receptor activation
Brian Kobilka, MD Professor
Department of Molecular and Cellular Physiology
Stanford University School of Medicine
Hélène Irwin Fagan Chair in Cardiology host: Stan Froehner abstract: G protein coupled receptors (GPCRs) conduct the majority of transmembrane responses to hormones and neurotransmitters, and mediate the senses of sight, smell and taste. The b2 adrenergic receptor (b2AR), the M2 muscarinic receptor and the mu-opioid receptor are prototypical Family A GPCRs. We have obtained three-dimensional structures of these receptors in inactive and active conformations, as well as a structure of the b2AR in complex with the G protein Gs. Comparison of these structures provides insights into common mechanisms for propagation of conformational changes from the agonist binding pocket to the G protein coupling interface. Crystal structures of inactive and active states may give the impression that GPCRs behave as simple two-state systems. However, cellular signaling assays reveal that many GPCRs signal through more than one G protein isoform, and through G protein independent pathways. This complex functional behavior provides evidence for the existence of multiple functionally distinct conformational states. We have used fluorescence, EPR and NMR spectroscopy to study the dynamic properties of several GPCRs. I will discuss what we these studies have taught us about allosteric regulation of GPCR structure by G proteins and ligands.
Mechanisms underlying flexible information flow across the brain Karel Svoboda, Ph.D. Director, Allen Institute: Abstract: Neural computation and behavior are produced by shifting configurations of multi-regional neural networks, implemented by dynamic coupling between brain regions. We...