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Conformational polymorphism of cyclosporin A
D Altschuh1, W Braun, J Kallen
1Institut de Biologie Moléculaire et Cellulaire du CNRS, Strasbourg, France.
Structure (London, England : 1993)
|October 15, 1994
Summary
Cyclosporin A (CsA) adopts different shapes when bound to cyclophilin A (CypA) versus antibody fragments (Fab). CypA selects a specific CsA conformation, while Fab binding involves mutual adaptation between CsA and the antibody.
Area of Science:
- Structural biology
- Immunology
- Biochemistry
Background:
- Cyclosporin A (CsA) is an immunosuppressive drug crucial in organ transplantation.
- CsA forms complexes with cyclophilin A (CypA) and antibody fragments (Fab), altering its conformation.
- Distinct CsA conformations exist in free form versus when bound to proteins.
Purpose of the Study:
- To compare the conformations of CsA when bound to CypA and Fab.
- To elucidate the structural basis of CsA-protein interactions.
Main Methods:
- X-ray crystallography
- Nuclear Magnetic Resonance (NMR) spectroscopy
Main Results:
- CsA-CypA complexes (X-ray and NMR) show similar CsA conformations.
- The Fab-bound CsA conformation differs significantly from the CypA-bound conformation.
- Both complexes involve five hydrogen bonds, but exhibit distinct side chain interactions and buried surface areas.
Conclusions:
- CypA likely binds a pre-existing CsA conformation.
- Fab-CsA complex formation suggests mutual structural adaptation between CsA and the antibody fragment.