A G(s)-selective analog of the receptor-mimetic peptide mastoparan binds to G(s)α in a kinked helical conformation

Mastoparan, a 14-residue peptide, stimulates GDP/GTP exchange on G proteins in a manner strikingly analogous to that of agonist-bound receptors. Presumably, the peptide structurally mimics a receptor's G protein-binding domain. We previously reported that mastoparan-X binds to α-subunits of G(i) and G(o) in a predominantly α-helical conformation [Sukumar, M., and Higashijima, T. (1992) J. Biol. Chem. 267, 21421-21424]. We have now developed an analogous peptide, INWKGIASM-α aminoisobutyryl (Aib)-RQVL-NH₂ (MP-S), which is a selective activator of G(s). We report the conformation of MP-S when it is bound to G(s)α, determined from distance geometry calculations based on transferred nuclear Overhauser effects (TRNOEs). The G(s)-bound conformation of MP-S is an α-helix that is kinked at residue 9. The conformations of MP-S when bound to G(i)α or G(o)α are similar to the G(s)α conformation. In contrast, the lipid-bound conformation of MP-S is a straight helix. On the basis of the G(s)-bound conformation of MP-S, directions for the design of G(s)-selective peptidergic mimics of receptors are suggested.