Structurally similar G protein complexes with β1-adrenergic receptor active state show differential binding kinetics, mediating selectivity

Abstract G protein-coupled receptors (GPCRs) bind to different G protein α-subtypes with varying degrees of selectivity. The mechanism by which GPCRs achieve this selectivity is still unclear. Using 13C methyl methionine and 19F NMR we investigated active states of β1AR agonist bound and in ternary complex with different G proteins in solution. We found the receptor in the ternary complexes adopted very similar conformations. In contrast the full agonist-bound receptor active state assumed a conformation different from previously characterized activation intermediates or from β1AR in ternary complexes. Assessing the kinetics of binding of the agonist-bound receptor with different G proteins we found the increased affinity of β1AR for Gs resulted from its much faster association with the receptor. Consequently, we suggest a kinetic-driven selectivity gate between canonical and secondary coupling which arises from differential favourability of G protein binding to the agonist-bound receptor active state.