DOI: 10.1073/pnas.192206699. Crystal structure of calcineurin–cyclophilin–cyclosporin shows common but distinct recognition of immunophilin

Crystal structure of calcineurin–cyclophilin–cyclosporin shows common but distinct recognition of immunophilin–drug complexes

10.1073/pnas.192206699

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, is the common target for two immunophilin–immunosuppressant complexes, cyclophilin A–cyclosporin A (CyPA-CsA) and FKBP–FK506. How the two structurally distinct immunophilin–drug complexes bind the same target has remained unknown. We report the crystal structure of calcineurin (CN) in complex with CyPA-CsA at 2.8-Å resolution. The CyPA-CsA complex binds to a composite surface formed by the catalytic and regulatory subunits of CN, where the complex of FK506 and its binding protein FKBP also binds. While the majority of the CN residues involved in the binding are common for both immunophilin-immunosuppressant complexes, a significant number of the residues are distinct. Unlike FKBP-FK506, CyPA-CsA interacts with Arg-122 at the active site of CN, implying direct involvement of CyPA-CsA in the regulation of CN catalysis. The simultaneous interaction of CyPA with both the composite surface and the active site of CN suggests that the composite surface may serve as a substrate recognition site responsible for the narrow substrate specificity of CN. The comparison of CyPA-CsA-CN with FKBP-FK506-CN significantly contributes to understanding the molecular basis of regulation of CN activity by the immunophilin–immunosuppressant.

Bibliography

Huai, Q., Kim, H.-Y., Liu, Y., Zhao, Y., Mondragon, A., Liu, J. O., & Ke, H. (2002). Crystal structure of calcineurinâcyclophilinâcyclosporin shows common but distinct recognition of immunophilinâdrug complexes. Proceedings of the National Academy of Sciences, 99(19), 12037â12042.

Authors 7

Qing Huai (first)
Hwa-Young Kim (additional)
Yudong Liu (additional)
Yingdong Zhao (additional)
Angelo Mondragon (additional)
Jun O. Liu (additional)
Hengming Ke (additional)

References 36 Referenced 234

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Dates

Type	When
Created	22 years, 11 months ago (Sept. 17, 2002, 12:40 p.m.)
Deposited	2 years, 4 months ago (April 24, 2023, 12:04 p.m.)
Indexed	1 month ago (July 24, 2025, 8:28 a.m.)
Issued	22 years, 11 months ago (Sept. 6, 2002)
Published	22 years, 11 months ago (Sept. 6, 2002)
Published Online	22 years, 11 months ago (Sept. 6, 2002)
Published Print	22 years, 11 months ago (Sept. 17, 2002)

Funders 0

None

BibTeX

@article{Huai_2002, title={Crystal structure of calcineurin–cyclophilin–cyclosporin shows common but distinct recognition of immunophilin–drug complexes}, volume={99}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.192206699}, DOI={10.1073/pnas.192206699}, number={19}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Huai, Qing and Kim, Hwa-Young and Liu, Yudong and Zhao, Yingdong and Mondragon, Angelo and Liu, Jun O. and Ke, Hengming}, year={2002}, month=sep, pages={12037–12042} }

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