Allosteric coupling from G protein to the agonist-binding pocket in GPCRs (original) (raw)

G protein-coupled receptors (GPCRs) remain the primary conduit by which cells detect environmental stimuli and communicate with each other 1. Upon activation by extracellular agonists, these seven transmembrane domain (7TM)-containing receptors interact with heterotrimeric G proteins to regulate downstream second messenger and/or protein kinase cascades 1. Crystallographic evidence from a prototypic GPCR, the β 2-adrenergic receptor (β 2 AR), in complex with its cognate G protein, Gs, has provided a model for how agonist binding promotes conformational changes that propagate through the GPCR and into the nucleotide binding pocket of the G protein α-subunit to catalyze GDP release, the key step required for GTP binding and activation of G proteins 2. The structure also offers hints on how G protein binding may, in turn, allosterically influence ligand binding. Here we provide functional evidence that G protein coupling to β 2 AR stabilizes a 'closed' receptor conformation characterized by restricted access to and egress from the hormone binding site. Surprisingly, the effects of G protein on the hormone binding site can be observed in the absence of a bound agonist, where G protein coupling driven by basal receptor activity impedes the association of agonists, partial agonists, antagonists and *