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

Qing Huai, Hwa Young Kim, Yudong Liu, Yingdong Zhao, Angelo Mondragon, Jun O. Liu, Hengming Ke

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)12037-12042
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number19
DOIs
StatePublished - Sep 17 2002

Keywords

  • FK506
  • FK506-binding protein
  • Immunosuppressants
  • Protein phosphatase
  • T cell

ASJC Scopus subject areas

  • General

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