What Makes a Kinase Promiscuous for Inhibitors?
What Makes a Kinase Promiscuous for Inhibitors?
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DOI：
10.1016/j.chembiol.2018.11.005
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发表时间：
2019-03-21
影响因子：
8.6
通讯作者：
Seeliger, Markus A.
中科院分区：
文献类型：
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作者：
Hanson, Sonya M.;Georghiou, George;Seeliger, Markus A.
由于ATP结合口袋的高度保守性，ATP竞争性激酶抑制剂通常结合几种激酶。通过对一个大型激酶组分析数据集的聚类分析，我们发现了一个由8种混杂激酶组成的聚类，它们平均结合的激酶抑制剂是数据集中其他398种激酶的5倍多。为了了解混杂抑制剂结合的结构基础，我们确定了受体酪氨酸激酶DDR 1与I型抑制剂达沙替尼和VX-680的共晶结构。令人惊讶的是，我们发现DDR 1以通常为II型抑制剂保留的非活性构象结合这些I型抑制剂。我们的计算和生物化学研究表明，DDR 1在这种非活性构象中异常稳定，为抑制剂滥交提供了一种机制解释。这种表型聚类分析提供了一种策略，以获得单独通过序列比较无法获得的功能见解。
ATP-competitive kinase inhibitors often bind several kinases due to the high conservation of the ATP binding pocket. Through clustering analysis of a large kinome profiling dataset, we found a cluster of eight promiscuous kinases that on average bind more than five times more kinase inhibitors than the other 398 kinases in the dataset. To understand the structural basis of promiscuous inhibitor binding, we determined the co-crystal structure of the receptor tyrosine kinase DDR1 with the type I inhibitors dasatinib and VX-680. Surprisingly, we find that DDR1 binds these type I inhibitors in an inactive conformation typically reserved for type II inhibitors. Our computational and biochemical studies show that DDR1 is unusually stable in this inactive conformation, giving a mechanistic explanation for inhibitor promiscuity. This phenotypic clustering analysis provides a strategy to obtain functional insights not available by sequence comparison alone.