Structural bioinformatics-based design of selective, irreversible kinase inhibitors
Structural bioinformatics-based design of selective, irreversible kinase inhibitors
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DOI：
10.1126/science1108367
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发表时间：
2005-05-27
期刊：
影响因子：
56.9
通讯作者：
Taunton, J
中科院分区：
文献类型：
--
作者：
Cohen, MS;Zhang, C;Taunton, J
491个人类蛋白激酶结构域的活性位点高度保守，这使得选择性抑制剂的设计成为一项艰巨的挑战。我们采用一种结构生物信息学方法，在p90核糖体蛋白S6激酶（RSK）活性位点的特定位置鉴定出两个选择性过滤器，一个苏氨酸和一个半胱氨酸。一种氟甲基酮抑制剂被设计用于利用这两个选择性过滤器，它能在哺乳动物细胞中有效地和选择性地使RSK1和RSK2失活。只有一个选择性过滤器的激酶对该抑制剂有抗性，但在通过基因引入第二个选择性过滤器后它们变得敏感。因此，两个能将RSK与其他蛋白激酶区分开来的氨基酸足以赋予对抑制剂的敏感性。
The active sites of 491 human protein kinase domains are highly conserved, which makes the design of selective inhibitors a formidable challenge. We used a structural bioinformatics approach to identify two selectivity filters, a threonine and a cysteine, at defined positions in the active site of p90 ribosomal protein S6 kinase (RSK). A fluoromethylketone inhibitor, designed to exploit both selectivity filters, potently and selectively inactivated RSK1 and RSK2 in mammalian cells. Kinases with only one selectivity filter were resistant to the inhibitor, yet they became sensitized after genetic introduction of the second selectivity filter. Thus, two amino acids that distinguish RSK from other protein kinases are sufficient to confer inhibitor sensitivity.