Conformational analysis of the C-terminal Gly-Leu-Met-NH2 tripeptide of substance P bound to the NK-1 receptor.
We examined the effect of simultaneously incorporating proline or proline-amino acid chimeras in positions 9, 10, and/or 11 of substance P, on the affinity for the two NK-1 binding sites and on second-messenger activation. Because these 3-substituted prolines constrain not only the (phi,psi) values of the peptide backbone, but also the chi space of the amino acid side chain, we were able to gather data on the structural requirements for high-affinity binding to the NK-1 receptor. We were able to confirm that this C-terminal component is crucial and that it should adopt an extended conformation close to a polyproline II structure when bound to the receptor. The partial additivity of these constraints, more specifically, for the NK-1M site, suggests that the peptide backbone flexibility around the hinge-point residue Gly9 is essential to subtly position crucial side chains.
Sagan
Sandrine
S
Synthèse, Structure et Fonction de Molécules Bioactives, Unite Mixte de Recherche 7613, Centre National de la Recherche Scientifique-Université Paris 6, Paris, France.
Quancard
Jean
J
Lequin
Olivier
O
Karoyan
Philippe
P
Chassaing
Gérard
G
Lavielle
Solange
S
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D016014:Linear Models; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D013373:Substance P / Q000737:chemistry* / Q000378:metabolism*
D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; D013373:Substance P; D011392:Proline