Structural basis of G proteing-coupled receptorg-G protein interactions

The interaction of G proteing-coupled receptors (GPCRs) with heterotrimeric G proteins represents one of the most fundamental biological processes. However, the molecular architecture of the GPCR-G protein complex remains poorly defined. In the present study, we applied a comprehensive GPCR-G protein α subunit (Gα) chemical cross-linking strategy to map a receptor-Gα interface, both before and after agonist-induced receptor activation. Using the M3 muscarinic acetylcholine receptor (M3R)-Gαq system as a model system, we examined the ability of ∼250 combinations of cysteine-substituted M3R and Gαq proteins to undergo cross-link formation. We identified many specific M3R-Gαq contact sites, in both the inactive and active receptor conformations, allowing us to draw conclusions regarding the basic architecture of the M3R-Gαq interface and the nature of the conformational changes following receptor activation. As heterotrimeric G proteins as well as most GPCRs share a high degree of structural homology, our findings should be of broad general relevance. © 2010 Nature America, Inc.