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 13 C methyl methionine and 19 F NMR we investigated active states of β 1 AR 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 β 1 AR in ternary complexes. Assessing the kinetics of binding of the agonist-bound receptor with different G proteins we found the increased affinity of β 1 AR for G s 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.