Crystal structure of human calcineurin complexed with cyclosporin a and human cyclophilin
Harrison, Stephen C.
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CitationJin, L., and S. C. Harrison. 2002. “Crystal Structure of Human Calcineurin Complexed with Cyclosporin A and Human Cyclophilin.” Proceedings of the National Academy of Sciences 99 (21): 13522–26. doi:10.1073/pnas.212504399.
AbstractCalcineurin (Cn), a Ca2+/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 Angstrom. 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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