Structural Insights into the Dynamic Process of G Protein Coupled Receptor Activation

Abstract

Research in my lab is directed at understanding the structural basis for the functional properties of G protein coupled receptors (GPCRs), which constitute the largest family of membrane proteins in the human genome. GPCRs conduct the majority of transmembrane responses to hormones and neurotransmitters, and mediate the senses of sight, smell and taste. The β2AR adrenoceptor (β2AR) is a prototypical Family A GPCR that mediates physiologic responses to adrenaline and noradrenaline. It regulates the activity of several distinct signaling pathways through both G protein dependent and G protein independent mechanisms. Like many GPCRs that respond to hormones and neurotransmitters, the β2AR exhibits modest basal activity in the absence of an agonist. This activity can be modulated by a spectrum of synthetic ligands ranging from inverse agonists, which suppress basal activity, to full agonists. We have obtained three-dimensional structures of the β2AR in inactive and active conformations, as well as a structure of the β2AR in complex with the G protein Gs. We have also used fluorescence, EPR and NMR spectroscopy to study the dynamic properties of the receptor, and to map ligand-specific conformational changes. I will discuss what we these studies have taught us about the structural basis of β2AR function.