The NMR structure of cyclosporin a bound to cyclophilin in aqueous solution

C. Weber, G. Wider, B. von Freyberg, Werner Braun, W. Braun, H. Widmer, K. Wüthrich

Research output: Contribution to journalArticle

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Abstract

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 15N- or 13C-labeling of cyclosporin A and heteronuclear spectral editing techniques. Sequence-specific assignments were obtained for all but one of the cyclosporin A proton resonances. With an input of 108 intramolecular NOEs and four vicinal 3 HNα 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 A. 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 A and the mean of the 120 conformers representing the NMR structure of cyclosporin A bound to cyclophilin is 2.5 Å.

Original languageEnglish (US)
Pages (from-to)6563-6574
Number of pages12
JournalBiochemistry
Volume30
Issue number26
StatePublished - 1991
Externally publishedYes

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Cyclophilins
Cyclosporine
Nuclear magnetic resonance
Conformations
Atoms
Chloroform
Labeling
Nuclear magnetic resonance spectroscopy
Protons
Hydrogen
Hydrogen bonds
Magnetic Resonance Spectroscopy
Crystal structure
Single crystals
Peptides
Geometry

ASJC Scopus subject areas

  • Biochemistry

Cite this

Weber, C., Wider, G., von Freyberg, B., Braun, W., Braun, W., Widmer, H., & Wüthrich, K. (1991). The NMR structure of cyclosporin a bound to cyclophilin in aqueous solution. Biochemistry, 30(26), 6563-6574.

The NMR structure of cyclosporin a bound to cyclophilin in aqueous solution. / Weber, C.; Wider, G.; von Freyberg, B.; Braun, Werner; Braun, W.; Widmer, H.; Wüthrich, K.

In: Biochemistry, Vol. 30, No. 26, 1991, p. 6563-6574.

Research output: Contribution to journalArticle

Weber, C, Wider, G, von Freyberg, B, Braun, W, Braun, W, Widmer, H & Wüthrich, K 1991, 'The NMR structure of cyclosporin a bound to cyclophilin in aqueous solution', Biochemistry, vol. 30, no. 26, pp. 6563-6574.
Weber C, Wider G, von Freyberg B, Braun W, Braun W, Widmer H et al. The NMR structure of cyclosporin a bound to cyclophilin in aqueous solution. Biochemistry. 1991;30(26):6563-6574.
Weber, C. ; Wider, G. ; von Freyberg, B. ; Braun, Werner ; Braun, W. ; Widmer, H. ; Wüthrich, K. / The NMR structure of cyclosporin a bound to cyclophilin in aqueous solution. In: Biochemistry. 1991 ; Vol. 30, No. 26. pp. 6563-6574.
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