Mechanism and Specificity of Pentachloropseudilin-mediated Inhibition of Myosin Motor Activity
Mechanism and Specificity of Pentachloropseudilin-mediated Inhibition of Myosin Motor Activity
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DOI：
10.1074/jbc.m111.239210
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发表时间：
2011-08-26
影响因子：
4.8
通讯作者：
Manstein, Dietmar J.
中科院分区：
文献类型：
--
作者：
Chinthalapudi, Krishna;Taft, Manuel H.;Manstein, Dietmar J.
在这里，我们报告说，天然化合物五氯地林（PCIP）作为一个可逆的和变构抑制剂的肌球蛋白ATP酶和运动活动。对于哺乳动物1类肌球蛋白，IC 50值在1至5 μ M的范围内，对于2类和5类肌球蛋白，IC 50值大于90 μ M，对于6类和7类肌球蛋白，未观察到抑制作用。我们发现，在哺乳动物细胞中，PCIP选择性抑制肌球蛋白-1c的功能。为了阐明PCIP诱导的变构偶联的结构基础和化合物抑制效力的异构体特异性差异，我们使用了多方面的方法，结合直接功能，晶体学和计算机模拟研究。我们的结果表明，PClP的变构抑制是由蛋白质动力学的整体变化以及催化位点和变构位点之间通过沿着保守通讯途径的一系列小的构象变化的直接通讯的综合效应介导的。
Here, we report that the natural compound pentachloropseudilin (PClP) acts as a reversible and allosteric inhibitor of myosin ATPase and motor activity. IC50 values are in the range from 1 to 5 mu M for mammalian class-1 myosins and greater than 90 mu M for class-2 and class-5 myosins, and no inhibition was observed with class-6 and class-7 myosins. We show that in mammalian cells, PClP selectively inhibits myosin-1c function. To elucidate the structural basis for PClP-induced allosteric coupling and isoform-specific differences in the inhibitory potency of the compound, we used a multifaceted approach combining direct functional, crystallographic, and in silico modeling studies. Our results indicate that allosteric inhibition by PClP is mediated by the combined effects of global changes in protein dynamics and direct communication between the catalytic and allosteric sites via a cascade of small conformational changes along a conserved communication pathway.