The solution structure of a cyclic endothelin antagonist, BQ-123, based on 1H-1H and 13C-1H three bond coupling constants

A cyclic pentapeptide endothelin antagonist, cyclo(dTrp-dAsp-Pro-dVal-Leu), recently reported (K. Ishikawa et al., 13th Am. Pept. Symp., Cambridge MA, 1991) has been studied by NMR spectroscopy and molecular modeling. A stable structure has been determined without the use of nuclear Overhauser effec...

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Bibliographic Details
Published in:FEBS letters 1992-03, Vol.300 (2), p.136-140
Main Authors: REILY, M. D, THANABAL, V, OMECINSKY, D. O, DUNBAR, J. B, DOHERTY, A. M, DEPUE, P. L
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Biological and medical sciences
Computer Simulation
Endothelins - antagonists & inhibitors
General pharmacology
Magnetic Resonance Spectroscopy
Medical sciences
Models, Molecular
Molecular Sequence Data
Peptides, Cyclic - chemistry
Pharmacology. Drug treatments
Physicochemical properties. Structure-activity relationships
Protein Conformation
Solutions
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Summary:A cyclic pentapeptide endothelin antagonist, cyclo(dTrp-dAsp-Pro-dVal-Leu), recently reported (K. Ishikawa et al., 13th Am. Pept. Symp., Cambridge MA, 1991) has been studied by NMR spectroscopy and molecular modeling. A stable structure has been determined without the use of nuclear Overhauser effects and is based primarily on homonuclear and heteronuclear three bond coupling constants. The 13C-edited TOCSY experiment is demonstrated at natural abundance and approximately 30 mM peptide concentrations. Three bond 13C-1H coupling constants obtained by this method are shown to reduce the ambiguity in phi angle determination which exists when only interproton coupling constants are used. Three out of four phi angles were determined uniquely by this method and the fourth was reduced to two possible values. The proline phi angle was determined to be -78 degrees based on the 3JH alpha, H beta and 3JH alpha, H beta coupling constants. Comparison of amide proton temperature dependence, chemical shifts and vicinal proton coupling constants in a 20% acetonitrile/80% water solvent mixture and in (CD3)2SO indicates that the structure is similar in both solvents.
ISSN:0014-5793
1873-3468