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Title: The NMR structure of cyclosporin A bound to cyclophilin in aqueous solution

Cyclosporin A bound to the presumed receptor protein cyclophilin was studied in aqueous solution at pH 6.0 by nuclear magnetic resonance spectroscopy using uniform {sup 15}N- or {sup 13}C-labeling of cyclosporin A and heteronuclear spectral editing techniques. With an input of 108 intramolecular NOEs and four vicinal {sup 3}J{sub HN{alpha}} coupling constants, the three-dimensional structure of cyclosporin A bound to cyclophilin was calculated with the distance geometry program DISMAN, and the structures resulting from 181 converged calculations were energy refined with the program FANTOM. A group of 120 conformers was selected on the basis of the residual constraint violations and energy criteria to represent the solution structure. The average of the pairwise root-mean-square distances calculated for the backbone atoms of the 120 structures was 0.58 {angstrom}. The structure represents a novel conformation of cyclosporin A, for which the backbone conformation is significantly different from the previously reported structures in single crystals and in chloroform solution. The structure has all peptide bonds in the trans form, contains no elements of regular secondary structure and no intramolecular hydrogen bonds, and exposes nearly all polar groups to its environment. The root-mean-square distance between the backbone atoms of the crystal structure of cyclosporin Amore » and the mean of the 120 conformers representing the NMR structure of cyclosporin A bound to cyclophilin is 2.5 {angstrom}.« less
Authors:
; ; ; ;  [1] ; ;  [2]
  1. (Eidgenoessische Technische Hochschule-Hoenggerberg, Zuerich (Switzerland))
  2. (Sandoz Pharma AG, Basel (Switzerland))
Publication Date:
OSTI Identifier:
5032348
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemistry; (United States); Journal Volume: 30:26
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; IMMUNOSUPPRESSIVE DRUGS; NUCLEAR MAGNETIC RESONANCE; AQUEOUS SOLUTIONS; D CODES; F CODES; GEOMETRY; MOLECULAR STRUCTURE; OVERHAUSER EFFECT; COMPUTER CODES; DISPERSIONS; DRUGS; MAGNETIC RESONANCE; MATHEMATICS; MIXTURES; RESONANCE; SOLUTIONS 550201* -- Biochemistry-- Tracer Techniques