Abstract
HUMAN cyclophilin A (CypA), a ubiquitous intracellular protein of 165 amino acids, is the major receptor for the cyclic undecapeptide immunosuppressant drug cyclosporin A (CsA)1,2, which prevents allograft rejection after transplant surgery3,4 and is efficacious in the field of autoimmune diseases5. CsA prevents T-cell proliferation by blocking the calcium-activated pathway leading to interleukin-2 transcription. Besides their ability to bind CsA, the cyclophilin isoforms6–8 also have peptidyl–prolyl isomerase activity9–11 and enhance the rate of protein folding12,13. The macrolide FK506 acts similarly to CsA and its cognate receptor FKBP also has peptidyl–prolyl isomerase activity14. Inhibition of this enzymatic activity alone is not sufficient to achieve immunosuppression15,16. A direct molecular interaction between the drug–immunophilin complex (CsA–CypA, or FK506–FKBP) and the phosphatase calcineurin, is responsible for modulating the T-cell receptor signal transduction pathway17,18. Here we describe the crystal structure of a decameric CypA–CsA complex. The crystallographic asymmetric unit is composed of a pentamer of 1:1 cyclophilin–cyclosporin complexes of rather exact non-crystallographic fivefold symmetry. The 2.8 Å electron density map is of high quality. The five independent cyclosporin molecules are clearly identifiable, providing an unambiguous picture of the detailed interactions between a peptide drug and its receptor. It broadly confirms the results of previous NMR, X-ray and modelling studies, but provides further important structural details which will be of use in the design of drugs that are analogues of CsA.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Harding, M. W., Handschumacher, R. E. & Speicher, D. W. J. biol. Chem. 261, 8547–8552 (1985).
Handschumacher, R. E., Harding, M. W., Rice, J., Drugge, R. J. & Speicher, D. W. Science 226, 544–547 (1984).
Calne, R. Y. et al. Lancet 2, 1323–1326 (1978).
Borel, J. F. Pharmac. Rev. 41, 259–371 (1989).
Feutren, G. Transplant. Proc. 24 (suppl. 2), 55–60 (1992).
Swanson, S. K.-H. et al. Proc. natn. Acad. Sci. U.S.A. 89, 3741–3745 (1992).
Price, E. R. et al. Proc. natn. Acad. Sci. U.S.A. 88, 1903–1907 (1991).
Friedman, J. & Weissman, I. Cell 66, 799–806 (1991).
Harrison, R. K. & Stein, R. L. J. Am. chem. Soc. 114, 3464–3471 (1992).
Kofron, J. L. Kuzmic, P., Kishore, V., Colon-Bonilla, E. & Rich, D. H. Biochemistry 30, 6127–6134 (1991).
Fischer, G., Wittmann-Liebold, B., Lang, K., Kiefhaber, T. & Schmid, F. X. Nature 337, 476–478 (1989).
Schoenbrunner, E. R. et al. J. biol. Chem. 266, 3630–3635 (1991).
Fransson, C. et al. FEBS Lett. 296, 90–94 (1992).
Rosen, M. K. & Schreiber, S. L. Angew. Chem. 104, 413–430 (1992).
Schreiber, S. L. Science 251, 283–287 (1991).
Sigal, N. H. & Al., E. J. exp. Med. 173, 619–628 (1991).
O'Keefe, S. J., Tamura, J., Kincaid, R. L., Tocci, M. J. & O'Neill, E. A. Nature 357, 692–694 (1992).
Clipstone, N. A. & Crabtree, G. R. Nature 357, 695–697 (1992).
Kallen, J. et al. Nature 353, 276–279 (1991).
Kallen, J. & Walkinshaw, M. D. FEBS Lett. 300, 286–290 (1992).
Ke, H., Zydowsky, L. D., Liu, J. & Walsh, C. T. Proc. natn. Acad. Sci. U.S.A. 88, 9483–9487 (1991).
Weber, C. et al. Biochemistry 30, 6563–6574 (1991).
Fesik, S. W. et al. Biochemistry 30, 6574–6583 (1991).
Spitzfaden, C. et al. FEBS Lett. 300, 291–300 (1992).
Fesik, S. W., Neri, P., Meadows, R., Olejniczak, E. T. & Gemmecker, G. J. Am. chem. Soc. 114, 3165–3166 (1992).
Gallion, S. & Ringe, D. Protein. Engng 5, 391–397 (1992).
Zurini, M. et al. FEBS Lett. 276, 63–66 (1990).
Tai, P. K., Albers, M. W., Chang, H., Faber, L. E. & Schreiber, S. L. Science 256, 1315–1318 (1992).
Langer, T. et al. Nature 356, 683–689 (1992).
Myles, D. A. A. et al. J. molec. Biol. 216, 491–496 (1990).
Wood, S. P. et al. J. molec. Biol. 202, 169–173 (1988).
Lindqvist, Y. J. Molec. Biol. 209, 151–166 (1989).
Brunger, A. T., Kuriyan, J. & Karplus, M. Science 235, 458–460 (1987).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Pflügl, G., Kallen, J., Schirmer, T. et al. X-ray structure of a decameric cyclophilin-cyclosporin crystal complex. Nature 361, 91–94 (1993). https://doi.org/10.1038/361091a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/361091a0
This article is cited by
-
PPIA rs6850: A > G single-nucleotide polymorphism is associated with raised plasma cyclophilin A levels in patients with coronary artery disease
Molecular and Cellular Biochemistry (2016)
-
Genome-wide analysis of alternative splicing in Volvox carteri
BMC Genomics (2014)
-
Cyclophilin A from Schistosoma japonicum promotes a Th2 response in mice
Parasites & Vectors (2013)
-
Cyclophilin 40 facilitates HSP90-mediated RISC assembly in plants
The EMBO Journal (2012)
-
Ricinus communis cyclophilin: functional characterisation of a sieve tube protein involved in protein folding
Planta (2008)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.