Solution-structure of a Peptide Designed to Mimic the C-terminal Hexapeptide of Endothelin

Abstract

Abstract The peptide: Ac-cyclo(Cys-His-Leu-Asp-Cys)-Ile-Trp-OH, has been designed by computer-aided molecular-modelling techniques to mimic the proposed α-helical conformation of the C-terminal hexapeptide of endothelin. Two-dimensional proton nuclear magnetic resonance spectra were acquired for the peptide dissolved in d6-DMSO or D2O-H2O and the distance and angle constraints incorporated into simulated annealing experiments. Conformers generated from the D2O-H2O data superposed on the corresponding main-chain atoms in the crystal structure of endothelin 1 and the solution structure of BQ-123 with root mean square co-ordinate differences of 0·9 Å and 0·77 Å, respectively. The peptide did not elicit antagonism of endothelin-induced in-vitro contractions of rabbit aorta (endothelin A receptor) or rabbit bronchus (endothelin B receptor) preparations. Because the peptide can adopt a conformer which closely matches the equivalent residues in the endothelin 1 crystal structure and in BQ-123, we suggest BQ-123 does not necessarily mimic the endothelin C-terminal region to achieve its antagonism, and that a helical conformation of the endothelin C-terminal hexapeptide does not favour its interaction at the endothelin B receptor.