The crystal structure of G(sα), the heterotrimeric G protein α subunit that stimulates adenylyl cyclase, was determined at 2.5 Å in a complex with guanosine 5'-O-(3-thio-triphosphate) (GTPγS). G(sα) is the prototypic member of a of GTP-binding proteins that regulate the activities of effectors in a hormone-dependent manner. Comparison of the structure of G(sα)·GTPγS with that of G(iα)·GTPγS suggest 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 stimutate the GTPase activity of G(sα). The βγ binding surface ofG(sα) is largely conserved in sequence and structure to that of G(iα), whereas differences in the surface formed by the carboxyl-terminal helix and the α4-β6 loop may mediate ceptor specificity.
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