Solution structure of a novel ETB receptor selective agonist ET1-21[Cys(Acm)(1,15), Aib(3,11), Leu(7)] by nuclear magnetic resonance spectroscopy andmolecular modelling

The solution structure of a biologically active modified linear endothelin- l analogue, ET1-21[Cys(Acm)(1,15), Aib(3,11), Leu(7)]. has been determined for the first time by two-dimensional nuclear magnetic resonance spectrosco py in a methanol-d(3)/water solvent mixture. Out of approximately one hundr ed linear peptide analogues tested by biological assay, this peptide, toget her with a dozen others, showed significant ETB selective agonist activity. Here we report the solution structure of an ETB selective agonist of a ful l-length, synthetic linear endothelin analogue. The calculated structures i ndicate that the peptide adopts an alpha-helical conformation between resid ues Ser(5)-His(16), whilst both N- and C-termini show no preferred conforma tion. These results suggest that the disulphide bridges normally associated with endothelin and sarafotoxin peptides may not necessarily be important for either ETB receptor binding activity or the formation of a helical conf ormation in solution.