Crystal Structure of the Adenylyl Cyclase Activator G s α

Abstract

The crystal structure of G s α , the heterotrimeric G protein α subunit that stimulates adenylyl cyclase, was determined at 2.5 Å in a complex with guanosine 5′- O -(3-thiotriphosphate) (GTPγS). G s α is the prototypic member of a family of GTP-binding proteins that regulate the activities of effectors in a hormone-dependent manner. Comparison of the structure of G s α ·GTPγS with that of G i α ·GTPγS suggests that their effector specificity is primarily dictated by the shape of the binding surface formed by the switch II helix and the α3-β5 loop, despite the high sequence homology of these elements. In contrast, sequence divergence explains the inability of regulators of G protein signaling to stimulate the GTPase activity of G s α . The βγ binding surface of G s α is largely conserved in sequence and structure to that of G i α , whereas differences in the surface formed by the carboxyl-terminal helix and the α4-β6 loop may mediate receptor specificity.