Conformational polymorphism of cyclosporin A. - Archive ouverte HAL
Journal Articles Structure / Struct Fold Des; Structure (Camb ) Year : 1994

Conformational polymorphism of cyclosporin A.

W. Braun
  • Function : Author
J. Kallen
  • Function : Author
V. Mikol
  • Function : Author
C. Spitzfaden
  • Function : Author
O. Vix
  • Function : Author
M. D. Walkinshaw
  • Function : Author
K. Wüthrich
  • Function : Author

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 395 A2 and 300 A2, respectively. However, the CsA-protein interactions involve rather different side chain contacts in the two complexes. CONCLUSIONS: 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.
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Dates and versions

hal-00265271 , version 1 (18-03-2008)

Identifiers

  • HAL Id : hal-00265271 , version 1
  • PUBMED : 7866747

Cite

Danièle Altschuh, W. Braun, J. Kallen, V. Mikol, C. Spitzfaden, et al.. Conformational polymorphism of cyclosporin A.. Structure / Struct Fold Des; Structure (Camb ), 1994, 2 (10), pp.963-72. ⟨hal-00265271⟩
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