A linear endothelin-1 analogue: solution structure of ET-1[Aib(1,3,11,15),Nle(7)] by nuclear magnetic resonance spectroscopy and molecular modelling

Two-dimensional nuclear magnetic resonance techniques and a combination of distance geometry and molecular dynamics calculations were utilised to dete rmine the three dimensional solution structure of an ET-1 analogue, ET-1[Ai b(1,3,11,5), Nle(7)], in a methanol-d(3)/water co-solvent. The modelled str ucture shows that the peptide folds into a consistent alpha-helical conform ation between residues Ser(4)-His(16) while the C-terminus prefers no fixed conformation. Our studies cofirm that the disulphide links which are norma lly associated with the endothelin family of neuropeptides are not importan t for the formation of a helical conformation in solution. This full length , modified, synthetic linear ET-1 analogue plays a vital role towards desig ning endothelin receptor agonists. Structure activity relationships are dis cussed in terms of the conformational features of the calculated structure. (C) 1999 Elsevier Science Ltd. All rights reserved.