Uncovering and Reprogramming G Protein Coupled Receptor Signaling

Abstract

G-protein-coupled receptors (GPCRs) constitute one of the largest classes of signaling membrane receptors and drug targets. GPCRs display a large diversity of constitutive activities and responses to extracellular stimuli defining their complex physiologies. Yet, how receptor sequences and structures encode these allosteric properties remains poorly understood and difficult to study in absence of high-resolution structural information for many GPCRs. To address this problem, my laboratory has developed computational techniques to model GPCRs, predict ligand-bound GPCR conformations from a large diversity of structural homologs and design membrane receptors with novel functions. Using these methods, we have rationally engineered structurally-uncharacterized GPCRs with novel ligand binding selectivities, allosteric regulation properties and self-association propensities. I will also discuss how, during the course of these studies, we uncovered novel molecular determinants of membrane protein functions.