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.
Sukumar
M
M
Department of Chemistry, University of Massachusetts at Amherst, 01003, USA. sukumar@chemistry.umass.edu
Ross
E M
EM
Higashijima
T
T
D015195:Drug Design; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000737:chemistry / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D008958:Models, Molecular; D015513:Oncogene Proteins / Q000378:metabolism*; D010455:Peptides; D011487:Protein Conformation; D014862:Wasp Venoms / Q000737:chemistry / Q000378:metabolism*
D036341:Intercellular Signaling Peptides and Proteins; D008823:Micelles; D015513:Oncogene Proteins; D010455:Peptides; D014862:Wasp Venoms; C037500:mastoparan; D019205:GTP-Binding Protein alpha Subunits, Gs