Solution-structure of a peptide designed to mimic the C-terminal hexapeptide of endothelin

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 a-heli cal conformation of the C-terminal hexapeptide of endothelin, Two-dimensional proton nuclear magnetic resonance spectra were acquired for the peptide dissolved in d(6)-DMSO or D2O-H2O and the distance and angle c onstraints incorporated into simulated annealing experiments. Conformers ge nerated from the D2O-H2O data superposed on the corresponding main-chain at oms in the crystal structure of endothelin 1 and the solution structure of BQ-123 with root mean square co-ordinate differences of 0.9 Angstrom and 0. 77 Angstrom, respectively. The peptide did not elicit antagonism of endothe lin-induced in-vitro contractions of rabbit aorta (endothelin A receptor) o r rabbit bronchus (endothelin B receptor) preparations. Because the peptide can adopt a conformer which closely matches the equival ent residues in the endothelin 1 crystal structure and in BQ-123, we sugges t BQ-123 does not necessarily mimic the endothelin C-terminal region to ach ieve its antagonism, and that a helical conformation of the endothelin C-te rminal hexapeptide does not favour its interaction at the endothelin B rece ptor.