title: The solution structure of a monocyclic analogue of endothelin [1,15 Aba]-ET-1, determined by 1H NMR spectroscopy.
abstract: The structure of [1,15 Aba]-ET-1 has been determined in aqueous acetonitrile solution (10% acetonitrile, 1.5% acetic acid). [1,15 Aba]-ET-1 is an analogue of endothelin (ET-1) in which the disulfide bridge linking residues 1 and 15 has been removed by replacement of the cysteine residues with the mimicking group alpha-aminobutyric acid (Aba). The structure has been determined by 1H NMR spectroscopy and simulated annealing calculations based on NOE constraints, 3JHN-H alpha scalar coupling constants, and amide-proton-exchange rates. Distance information was extracted from 2D NOESY spectra using full-relaxation matrix techniques (utilizing the program DISCON). The structure can be described in terms of three defined segments: a type I beta-turn over residues 5-8, a helix over residues 9-16, and a structured C-terminus over residues 17-21. The data indicate that some conformational averaging occurs throughout the peptide, particularly for residues 1-4 in the N-terminus, where no preferred conformation is present. The structure is compared with those previously reported for native ET-1. In general, removal of the disulfide bridge does not cause a major structural change in the helical and turn regions of the sequence, but increased structural disorder is noted at the N-terminus. The implications of the monocyclic analogue's conformation for the pharmacological activity and the ETA/ETB selectivity of the endothelin family of peptides and analogues are described. The N-terminus is proposed to be a key structural region for differentiation of binding activity at the ETA and ETB receptor sites.
authors.affiliation: School of Pharmaceutical Chemistry, Victorian College of Pharmacy, Monash University, Parkville, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Coles
authors.forename: S L
authors.initials: SL
authors.lastname: Munro
authors.forename: D J
authors.initials: DJ
authors.lastname: Craik
mesh_terms: D000595:Amino Acid Sequence; D019332:Endothelin-1 / Q000031:analogs & derivatives; D016232:Endothelins / Q000737:chemistry*; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012996:Solutions
chemical_list: D019332:Endothelin-1; D016232:Endothelins; D012996:Solutions; C086215:endothelin-1, Aba(1,15)-