Synthesis and solution conformation of c(D-Trp-D-Cys(SO3-Na+)-Pro-D-Val-Leu), a potent endothelin-A receptor antagonist.
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.
Bogusky
M J
MJ
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania.
Brady
S F
SF
Sisko
J T
JT
Nutt
R F
RF
Smith
G M
GM
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
D010456:Peptides, Cyclic; D012996:Solutions; C072485:cyclo(sulfoalanyl-prolyl-valyl-leucyl-tryptophyl)