Solution-structure of a peptide designed to mimic the C-terminal hexapeptide of endothelin.
Ac-cyclo(Cys-His-Leu-Asp-Cys)-Ile-Trp-OH, has been designed by computer-aided molecular-modelling techniques to mimic the proposed alpha-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 0.9A and 0.77A, 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.
Van der Walle
C F
CF
Pharmacy Department, King's College, London, UK.
Bansal
S
S
Barlow
D J
DJ
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D016232:Endothelins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D011817:Rabbits; D017466:Receptors, Endothelin / Q000187:drug effects*; D012996:Solutions
D016232:Endothelins; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; D012996:Solutions; C115796:acetyl-cyclo(cysteinyl-histidyl-leucyl-aspartyl-cysteinyl)isoleucyl-tryptophan