Structural basis for induced-fit binding of Rho-kinase to the inhibitor Y-27632
Structural basis for induced-fit binding of Rho-kinase to the inhibitor Y-27632
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DOI：
10.1093/jb/mvj172
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发表时间：
2006-09-01
影响因子：
2.7
通讯作者：
Hakoshima, Toshio
中科院分区：
文献类型：
--
作者：
Yamaguchi, Hiroto;Miwa, Yukiko;Hakoshima, Toshio
Rho 激酶是细胞骨架事件调节的主要参与者，也是治疗血管和神经系统疾病的有前途的药物靶点。在这里，我们报告了与特异性抑制剂 Y-27632 复合的 Rho 激酶催化结构域的晶体结构。与该抑制剂结合的 PKA 结构的比较揭示了一种潜在的诱导拟合结合模式，可以通过磷酸盐结合环来适应。这种结合模式类似于在 Rho-激酶-法舒地尔复合物中观察到的结合模式。结构数据库搜索表明，磷酸盐结合环下方存在一个口袋，有利于与小芳环结合。这种环基团的引入可能会产生一种对现有蛋白激酶抑制剂的新修饰方案，以提高结合能力。
Rho-kinase is a main player in the regulation of cytoskeletal events and a promising drug target in the treatment of both vascular and neurological disorders. Here we report the crystal structure of the Rho-kinase catalytic domain in complex with the specific inhibitor Y-27632. Comparison with the structure of PKA bound to this inhibitor revealed a potential induced-fit binding mode that can be accommodated by the phosphate binding loop. This binding mode resembles to that observed in the Rho-kinase-fasudil complex. A structural database search indicated that a pocket underneath the phosphate-binding loop is present that favors binding to a small aromatic ring. Introduction of such a ring group might spawn a new modification scheme of pre-existing protein kinase inhibitors for improved binding capability.