Crystal structure of human calcineurin complexed with cyclosporin A and human cyclophilin.
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.
D001665:Binding Sites; D019703:Calcineurin / Q000737:chemistry* / Q000235:genetics; D065095:Calcineurin Inhibitors; D018360:Crystallography, X-Ray; D021983:Cyclophilins / Q000737:chemistry*; D016572:Cyclosporine / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000494:pharmacology; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D055672:Static Electricity; D013329:Structure-Activity Relationship; D016559:Tacrolimus / Q000737:chemistry; D022021:Tacrolimus Binding Proteins / Q000737:chemistry
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D046911:Macromolecular Substances; D011994:Recombinant Proteins; D016572:Cyclosporine; D019703:Calcineurin; D021983:Cyclophilins; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus