Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes
Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes
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DOI：
10.1073/pnas.192206699
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发表时间：
2002-09-17
影响因子：
11.1
通讯作者：
Ke, HM
中科院分区：
文献类型：
--
作者：
Huai, Q;Kim, HY;Ke, HM
钙调磷酸酶是一种Ca 2 +/钙调蛋白依赖性蛋白磷酸酶，是两种亲免素-免疫抑制剂复合物亲环素A-环孢菌素A（CyPA-CsA）和FKBP-FK 506的共同靶点。这两种结构不同的亲免疫素-药物复合物如何结合相同的靶点仍然是未知的。我们报告的晶体结构的钙调神经磷酸酶（CN）在复杂的CyPA-CsA在2.8埃分辨率。CyPA-CsA复合物结合到由CN的催化和调节亚基形成的复合物表面，其中FK 506及其结合蛋白FKBP的复合物也结合。虽然参与结合的大多数CN残基对于两种亲免素-免疫抑制剂复合物是共同的，但大量残基是不同的。与FKBP-FK 506不同，CyPA-CsA在CN的活性位点与Arg-122相互作用，这意味着CyPA-CsA直接参与CN催化的调节。CyPA与复合材料表面和CN的活性位点的同时相互作用表明，复合材料表面可以作为负责CN的窄底物特异性的底物识别位点。CyPA-CsA-CN与FKBP-FK 506-CN的比较显著有助于理解亲免素-免疫抑制剂调节CN活性的分子基础。
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-Angstrom 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.