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

32 Citations (Scopus)

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 - 1994
Externally publishedYes

Fingerprint

Cyclosporine
Cyclophilin A
X Ray Crystallography
Proteins
X-Rays
Cyclophilins
Immunoglobulin Fragments
Immunosuppressive Agents
Hydrogen
Ligands
Transplants

Keywords

  • antibody recognition
  • cyclophilin
  • cyclosporin A
  • ligand binding

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

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

Conformational polymorphism of cyclosporin A. / Altschuh, Danièle; Braun, Werner; Kallen, Joerg; Mikol, Vincent; Spitzfaden, Claus; Thierry, Jean Claude; Vix, Olivier; Walkinshaw, Malcolm D.; Wüthrich, Kurt.

In: Structure, Vol. 2, No. 10, 1994, p. 963-972.

Research output: Contribution to journalArticle

Altschuh, D, Braun, W, Kallen, J, Mikol, V, Spitzfaden, C, Thierry, JC, Vix, O, Walkinshaw, MD & Wüthrich, K 1994, 'Conformational polymorphism of cyclosporin A', Structure, vol. 2, no. 10, pp. 963-972. https://doi.org/10.1016/S0969-2126(94)00098-0
Altschuh D, Braun W, Kallen J, Mikol V, Spitzfaden C, Thierry JC et al. Conformational polymorphism of cyclosporin A. Structure. 1994;2(10):963-972. https://doi.org/10.1016/S0969-2126(94)00098-0
Altschuh, Danièle ; Braun, Werner ; Kallen, Joerg ; Mikol, Vincent ; Spitzfaden, Claus ; Thierry, Jean Claude ; Vix, Olivier ; Walkinshaw, Malcolm D. ; Wüthrich, Kurt. / Conformational polymorphism of cyclosporin A. In: Structure. 1994 ; Vol. 2, No. 10. pp. 963-972.
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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{\aa} and 300{\aa}, 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.",
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AU - Vix, Olivier

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N2 - 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.

AB - 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.

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