CRYSTAL-STRUCTURE OF THE ADENYLYL-CYCLASE ACTIVATOR G(S-ALPHA)

The crystal structure of G(S alpha), the heterotrimeric G protein alph a subunit that stimulates adenylyl cyclase, was determined at 2.5 Angs trom in a complex with guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S). G(S alpha) is the prototypic member of a family of GTP-binding pro teins that regulate the activities of effectors in a hormone-dependent manner. Comparison of the structure of G(S alpha).GTP gamma S with th at of G(i alpha).GTP gamma S suggests that their effector specificity is primarily dictated by the shape of the binding surface formed by th e switch II helix and the alpha 3-beta 5 loop, despite the high sequen ce homology of these elements. In contrast, sequence divergence explai ns the inability of regulators of G protein signaling to stimulate the GTPase activity of G(S alpha). The beta gamma binding surface of G(S alpha) is largely conserved in sequence ana structure to that of G(i a lpha), whereas differences in the surface formed by the carboxyl-termi nal helix and the alpha 4-beta 6 loop may mediate receptor specificity .