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Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13522-6. Epub 2002 Sep 30.

Crystal structure of human calcineurin complexed with cyclosporin A and human cyclophilin.

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  • 1Department of Molecular and Cellular Biology, and Howard Hughes Medical Institute, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA.


Calcineurin (Cn), a Ca(2+)/calmodulin-dependent Ser/Thr protein phosphatase, is an important participant in signaling pathways that activate T cells. It is the target of the immunosuppressive drugs cyclosporin A (CsA) and FK506. These drugs bind proteins known as cyclophilin (Cyp) and FK506-binding protein, respectively, and the drug-protein complexes in turn inhibit Cn. We report the crystal structure of a Cyp/CsA/Cn ternary complex, determined to a resolution of 3.1 A. Residues 3-9 of CsA, particularly N-methyl leucines 4 and 6, and Trp-121 of Cyp form a composite surface for interaction with Cn. The hydrophobic interface buries two hydrogen bonds. The structure accounts clearly for the effects of mutations in Cn on CsA-resistance and for the way modifications of CsA alter immunosuppressive activity.

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