title: Synthesis and solution conformation of c(D-Trp-D-Cys(SO3-Na+)-Pro-D-Val-Leu), a potent endothelin-A receptor antagonist.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania.
authors.forename: M J
authors.initials: MJ
authors.lastname: Bogusky
authors.forename: S F
authors.initials: SF
authors.lastname: Brady
authors.forename: J T
authors.initials: JT
authors.lastname: Sisko
authors.forename: R F
authors.initials: RF
authors.lastname: Nutt
authors.forename: G M
authors.initials: GM
authors.lastname: Smith
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry*; D012996:Solutions
chemical_list: D010456:Peptides, Cyclic; D012996:Solutions; C072485:cyclo(sulfoalanyl-prolyl-valyl-leucyl-tryptophyl)