A Gs-selective analog of the receptor-mimetic peptide mastoparan binds to Gs alpha 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 alpha-subunits of Gi and Go in a predominantly alpha-helical conformation [Sukumar, M., & Higashijima, T. (1992) J. Biol. Chem. 267, 21421-21424]. We have now developed an analogous peptide, INWKGIASM-alpha-aminoisobutyryl (Aib)-RQVL-NH2 (MP-S), which is a selective activator of Gs. We report the conformation of MP-S when it is bound to Gs alpha, determined from distance geometry calculations based on transferred nuclear Overhauser effects (TRNOEs). The Gs-bound conformation of MP-S is an alpha-helix that is kinked at residue 9. The conformations of MP-S when bound to Gi alpha or Go alpha are similar to the Gs alpha-bound conformation. In contrast, the lipid-bound conformation of MP-S is a straight helix. On the basis of the Gs-bound conformation of MP-S, directions for the design of Gs-selective peptidergic mimics of receptors are suggested.