STRUCTURE-BASED DESIGN OF A CYCLOPHILIN-CALCINEURIN BRIDGING LIGAND
STRUCTURE-BASED DESIGN OF A CYCLOPHILIN-CALCINEURIN BRIDGING LIGAND
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DOI：
10.1126/science.8211144
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发表时间：
1993-10-08
期刊：
影响因子：
56.9
通讯作者：
SCHREIBER, SL
中科院分区：
文献类型：
--
作者：
ALBERG, DG;SCHREIBER, SL
当与其受体结合时采用特定构象的柔性配体的亲和力应通过适当使用构象限制来增加。通过确定蛋白质-配体复合物的结构，这种限制原则上可以以合理的方式设计到结合的配体中。免疫抑制剂环孢菌素A（CsA）的三环变体（TCsA）通过形成亲环素-CsA-钙调神经磷酸酶复合物来抑制T淋巴细胞的增殖。在TCSA的构象限制似乎是负责其亲环蛋白和钙调神经磷酸酶相对于CsA更大的亲和力。
The affinity of a flexible ligand that adopts a specific conformation when bound to its receptor should be increased with the appropriate use of conformational restraints. By determining the structure of protein-ligand complexes, such restraints can in principle be designed into the bound ligand in a rational way. A tricyclic variant (TCsA) of the immunosuppressant cyclosporin A (CsA), which inhibits the proliferation of T lymphocytes by forming a cyclophilin-CsA-calcineurin complex, was designed with the known three-dimensional structure of a cyclophilin-CsA complex. The conformational restraints in TCsA appear to be responsible for its greater affinity for cyclophilin and calcineurin relative to CsA.