CRYSTAL-STRUCTURE OF MURINE CYCLOPHILIN-C COMPLEXED WITH IMMUNOSUPPRESSIVE DRUG CYCLOSPORINE-A
CRYSTAL-STRUCTURE OF MURINE CYCLOPHILIN-C COMPLEXED WITH IMMUNOSUPPRESSIVE DRUG CYCLOSPORINE-A
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DOI：
10.1073/pnas.90.24.11850
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发表时间：
1993-12-15
影响因子：
11.1
通讯作者：
FRIEDMAN, J
中科院分区：
文献类型：
--
作者：
KE, HM;ZHAO, YD;FRIEDMAN, J
亲环素是免疫抑制药物环孢菌素A（CsA）的细胞受体。亲环素C（CyPC）在小鼠肾脏中高度表达，使其成为CsA肾毒性作用的潜在介质。与CsA复合的鼠CyPC的结构已被解析并在1.64埃分辨率下精确到0.197的R因子。CyPC-CsA结构与未连接的亲环素A（CyPA）的叠加显示了三个环的显著迁移：Gln-179至Thr-189，Asp-47至Lys-49，Met-170至Ile-176。环Gln-179到Thr-189到CsA结合位点的接近性可以解释77-kDa糖蛋白CyPC结合蛋白（CyCAP）与CyPC的独特结合。CsA与CyPC的结合类似于CsA与人T细胞亲环素A（CyPA）的结合。然而，CsA与CyPC结合时的构象与与CyPA结合时的构象显著不同。这些差异可能反映了CsA与不同蛋白结合时的构象变化。或者，先前的低分辨率CyPA-CsA结构可能无法提供足够的细节与CyPC-CsA结构进行比较。
Cyclophilin is a cellular receptor for the immunosuppressive drug cyclosporin A (CsA). Cyclophilin C (CyPC) is highly expressed in murine kidney, making it a potential mediator of the nephrotoxic effects of CsA. The structure of murine CyPC complexed with CsA has been solved and refined to an R factor of 0.197 at a 1.64-angstrom resolution. Superposition of the CyPC-CsA structure with the unligated cyclophilin A (CyPA) revealed significant migration of three loops: Gln-179 to Thr-189, Asp-47 to Lys-49, and Met-170 to Ile-176. The proximity of the loop Gln-179 to Thr-189 to the CsA binding site may account for the unique binding of a 77-kDa glycoprotein, CyPC binding protein (CyCAP), to CyPC. The binding of CsA to CyPC is similar to that of CsA to human T-cell cyclophilin A (CyPA). However, the conformation of CsA when bound to CyPC is significantly different from that when bound to CyPA. These differences may reflect conformational variation of CsA when bound to different proteins. Alternatively, the previous CyPA-CsA structure at low resolution may not provide sufficient details for a comparison with the CyPC-CsA structure.