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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A Conserved Protonation-dependent Switch Controls Drug Binding In The Abi Kinase
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A Conserved Protonation-dependent Switch Controls Drug Binding In The Abi Kinase

机译：保守的质子化依赖开关控制Abi激酶中的药物结合。

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摘要

In many protein kinases, a characteristic conformational change (the "DFG flip") connects catalytically active and inactive conformations. Many kinase inhibitors-including the cancer drug imatinib-selectively target a specific DFG conformation, but the function and mechanism of the flip remain unclear. Using long molecular dynamics simulations of the Abl kinase, we visualized the DFG flip in atomic-level detail and formulated an energetic model predicting that pro-tonation of the DFG aspartate controls the flip. Consistent with our model's predictions, we demonstrated experimentally that the kinetics of imatinib binding to Abl kinase have a pH dependence that disappears when the DFG aspartate is mutated. Our model suggests a possible explanation for the high degree of conservation of the DFG motif: that the flip, modulated by electrostatic changes inherent to the catalytic cycle, allows the kinase to access flexible conformations facilitating nucleotide binding and release.
机译：在许多蛋白激酶中，特征性构象变化（“ DFG翻转”）将催化活性和非活性构象连接起来。许多激酶抑制剂（包括抗癌药伊马替尼）选择性靶向特定的DFG构象，但翻转的功能和机制仍不清楚。使用Abl激酶的长分子动力学模拟，我们以原子水平的细节可视化了DFG翻转，并制定了一个能量模型，预测DFG天冬氨酸的质子控制翻转。与模型的预测一致，我们通过实验证明了伊马替尼与Abl激酶结合的动力学具有pH依赖性，当DFG天冬氨酸突变时，pH依赖性消失。我们的模型为DFG基序的高度保守性提出了一种可能的解释：由催化循环固有的静电变化调节的翻转使激酶能够访问有助于核苷酸结合和释放的柔性构象。

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