Conformational polymorphism of cyclosporin A

Danièle Altschuh, Werner Braun, Joerg Kallen, Vincent Mikol, Claus Spitzfaden, Jean Claude Thierry, Olivier Vix, Malcolm D. Walkinshaw, Kurt Wüthrich

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Background: Cyclosporin A (CsA) is a cyclic undecapeptide fungal metabolite with immunosuppressive properties, widely used in transplant surgery. It forms a tight complex with the ubiquitous 18 kDa cytosolic protein cyclophilin A (CypA). The conformation of CsA in this complex, as studied by NMR or X-ray crystallography, is very different from that of free CsA. Another, different conformation of CsA has been found in a complex with an antibody fragment (Fab). Results A detailed comparison of the conformations of experimentally determined structures of protein-bound CsA is presented. The X-ray and NMR structures of CsA-CypA complexes are similar. The Fab-bound conformation of CsA, as determined by X-ray crystallography, is significantly different from the cyclophilin-bound conformation. The protein-CsA interactions in both the Fab and CypA complexes involve five hydrogen bonds, and the buried CsA surface areas are 395å and 300å, respectively. However, the CsA-protein interactions involve rather different side chain contacts in the two complexes. Conclusion The structural results presented here are consistent with CypA recognizing and binding a population of CsA molecules which are in the required CypA-binding conformation. In contrast, the X-ray structures of the Fab complex with CsA suggest that in this case there is mutual adaptation of both receptor and ligand during complex formation.

Original languageEnglish (US)
Pages (from-to)963-972
Number of pages10
JournalStructure
Volume2
Issue number10
DOIs
StatePublished - Oct 1994
Externally publishedYes

Keywords

  • antibody recognition
  • cyclophilin
  • cyclosporin A
  • ligand binding

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Altschuh, D., Braun, W., Kallen, J., Mikol, V., Spitzfaden, C., Thierry, J. C., Vix, O., Walkinshaw, M. D., & Wüthrich, K. (1994). Conformational polymorphism of cyclosporin A. Structure, 2(10), 963-972. https://doi.org/10.1016/S0969-2126(94)00098-0