Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2
Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2
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DOI：
10.1016/j.chembiol.2021.01.003
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发表时间：
2021-05-20
影响因子：
8.6
通讯作者：
Knapp, Stefan
中科院分区：
文献类型：
--
作者：
Berger, Benedict-Tilman;Amaral, Marta;Knapp, Stefan
越来越多的证据表明，延长药物-靶标停留时间与提高药物疗效之间存在显著相关性。在这里，我们报告了两个密切相关的激酶：粘着斑激酶（FAK）和富含脯氨酸的酪氨酸激酶2（PYK 2）之间的动力学选择性的结构原理。我们发现，缓慢解离的FAK抑制剂诱导FAK的DFG基序的螺旋结构，但不是PYK 2。结合动力学数据，高分辨率的结构和诱变数据支持抑制剂与DFG-螺旋区域的疏水相互作用的作用，提供了从FAK的缓慢解离速率和PYK 2的动力学选择性的结构原理。我们的实验数据与计算的相对停留时间从分子模拟，支持合理优化配体停留时间的可行策略。我们认为，蛋白质结构的流动性和配体诱导的效果之间的相互作用是一个关键的调节剂的动力学选择性抑制剂FAK与PYK 2。
There is increasing evidence of a significant correlation between prolonged drug-target residence time and increased drug efficacy. Here, we report a structural rationale for kinetic selectivity between two closely related kinases: focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). We found that slowly dissociating FAK inhibitors induce helical structure at the DFG motif of FAK but not PYK2. Binding kinetic data, high-resolution structures and mutagenesis data support the role of hydrophobic interactions of inhibitors with the DFG-helical region, providing a structural rationale for slow dissociation rates from FAK and kinetic selectivity over PYK2. Our experimental data correlate well with computed relative residence times from molecular simulations, supporting a feasible strategy for rationally optimizing ligand residence times. We suggest that the interplay between the protein structural mobility and ligand-induced effects is a key regulator of the kinetic selectivity of inhibitors of FAK versus PYK2.