THE CHEMISTRY OF SIGNAL-TRANSDUCTION
THE CHEMISTRY OF SIGNAL-TRANSDUCTION
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DOI：
10.1073/pnas.92.1.56
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发表时间：
1995-01-03
影响因子：
11.1
通讯作者：
CLARDY, J
中科院分区：
文献类型：
--
作者：
CLARDY, J
包括化学生态学在内的几个学科试图了解生物系统中信息传递的分子基础，一般的分子策略开始出现。这些策略通常是通过仔细分析天然产品及其生物效应而发现的。环孢菌素A、FK506和雷帕霉素是由土壤微生物产生的，正在被用作或被考虑作为临床免疫抑制剂。它们通过与结合蛋白FK506和环孢素A(CsA)的雷帕霉素和亲环素A(CyPA)形成结合蛋白FKBP12的复合体来中断T细胞的细胞质部分信号。这个复合体反过来抑制一个蛋白质靶点，而最被理解的靶点是钙调神经磷酸酶，它被FK506-FKBP12和CyPA-CsA抑制。突变和结构研究有助于确定FK506-FKBP12如何与钙调神经磷酸酶相互作用，并对这些研究的结果进行了总结。FK506与FKBP12的强结合表明FK506是FKBP12的天然配体。还描述了探索这种拟态的合成和结构研究。
Several disciplines, including chemical ecology, seek to understand the molecular basis of information transfer in biological systems, and general molecular strategies are beginning to emerge. Often these strategies are discovered by a careful analysis of natural products and their biological effects. Cyclosporin A, FK506, and rapamycin are produced by soil microorganisms and are being used or considered as clinical immunosuppressive agents. They interrupt the cytoplasmic portion of T-cell signaling by forming a complex with a binding protein-FKBP12 in the case of FK506 and rapamycin and cyclophilin A (CyPA) in the case of cyclosporin A (CsA). This complex in turn inhibits a protein target, and the best understood target is calcineurin, which is inhibited by FK506-FKBP12 and CyPA-CsA. Mutational and structural studies help define how FK506-FKBP12 interacts with calcineurin, and the results of these studies are summarized. The existence of strong FK506-FKBP12 binding suggests that FK506 is mimicking some natural ligand for FKBP12. Synthetic and structural studies to probe this mimicry are also described.