Abstract
THE protein cyclophilin is the major intracellular receptor for the immunosuppressive drug cyclosporin A (ref. 1). Cyclosporin A acts as an inhibitor of T-cell activation and can prevent graft rejection in organ and bone marrow transplantation2. Cyclophilin may be responsible for mediating this immunosuppressive response. Cyclophilin also catalyses the interconversion of the cis and trans isomers of the peptidyl–prolyl amide bonds of peptide and protein substrates3,4. Here we report the X-ray crystal structure of human recombinant cyclophilin complexed with a tetrapeptide and the identification, by nuclear magnetic resonance spectroscopy, of the specific binding site for cyclosporin A. Cyclophilin has an eight-stranded antiparallel β-barrel structure. The prolyl isomerase substrate-binding site is coincident with the cyclosporin-binding site. These results may help to provide a structural basis for rationalizing the immunosuppressive function of the cyclosporin–cyclophilin system and will also be important in the design of improved immunosuppressant drugs.
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Kallen, J., Spitzfaden, C., Zurini, M. et al. Structure of human cyclophilin and its binding site for cyclosporin A determined by X-ray crystallography and NMR spectroscopy. Nature 353, 276–279 (1991). https://doi.org/10.1038/353276a0
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DOI: https://doi.org/10.1038/353276a0
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