Synthesis and solution conformation of c(D-Trp-D-Cys(SO3-Na+)-Pro-D-Val-Leu), a potent endothelin-A receptor antagonist

• Published in: International journal of peptide and protein research Vol. 42; no. 2; p. 194
• Main Authors: Bogusky, M J, Brady, S F, Sisko, J T, Nutt, R F, Smith, G M
• Format: Journal Article
• Language: English
• Published: Denmark 01.08.1993
• Subjects: Amino Acid Sequence; Computer Simulation; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Molecular Sequence Data; Peptides, Cyclic - chemistry; Solutions
• ISSN: 0367-8377
• DOI: 10.1111/j.1399-3011.1993.tb00496.x

The endothelin family of polypeptides are known to exert potent physiological effects which include cardiovascular regulation. The solution conformation and dynamics of c(D-Trp-D-Cys(SO3-Na+)-Pro-D-Val-Leu), a potent endothelin-A receptor-selective antagonist, were characterized in aqueous solution by NMR spectroscopy and molecular modeling. NMR-derived conformational constraints were combined with computer-assisted molecular modeling using distance geometry calculations and energy minimization. The pentapeptide backbone is shown to adopt a single conformation in solution comprising a type II beta-turn and an inverse gamma-turn, with each residue in the trans conformation. Molecular dynamics were explored using relaxation measurements and low-temperature studies, and indicate that the peptide backbone is highly constrained with little conformational mobility present.