NMR and computational evidence that high-affinity bradykinin receptor antagonists adopt C-terminal beta-turns.
Three tetrapeptides were prepared, each corresponding to the four C-terminal amino acid residues of highly potent, second-generation bradykinin receptor antagonists. The tetrapeptides are (IA) Ser-D-Phe-Oic-Arg, (IIA) Ser-D-Tic-Oic-Arg, and (IIIA) Ser-D-Hype(trans-propyl)-Oic-Arg. Solution conformations for each were determined by incorporating interproton distance restraints, determined by 2D NMR experiments performed in water at neutral pH, into a series of distance geometry/simulated annealing model building calculations. Similarly, systematic conformational analyses were performed for each using molecular mechanics calculations. Both the NMR-derived structures, as well as the calculated structures, are shown to adopt a beta-turn as the primary conformation. Excellent agreement between the predicted structures and the NMR-derived structures is demonstrated. Aside from being the first examples of linear tetrapeptides reported to be ordered in aqueous solvent, the results presented support the hypothesis that high-affinity bradykinin receptor antagonists must adopt C-terminal beta-turn conformations.
Kyle
D J
DJ
Scios Nova Inc., Baltimore, Maryland 21224.
Blake
P R
PR
Smithwick
D
D
Green
L M
LM
Martin
J A
JA
Sinsko
J A
JA
Summers
M F
MF
D000595:Amino Acid Sequence; D000818:Animals; D006168:Guinea Pigs; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018002:Receptors, Bradykinin; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D018002:Receptors, Bradykinin; D017981:Receptors, Neurotransmitter; C081288:seryl-phenylalanyl-octahydroindole-2-carbonyl-arginine; C081285:seryl-HYPE(transpropyl)-octahydroindole-2-carbonyl-arginine; C081286:seryl-tetrahydroisoquinolinecarbonyl-octahydroindole-2-carbonyl-arginine