Structural Basis for the Inhibition of the Autophosphorylation Activity of HK853 by Luteolin
Structural Basis for the Inhibition of the Autophosphorylation Activity of HK853 by Luteolin
复制标题
木犀草素抑制 HK853 自磷酸化活性的结构基础
DOI：
10.3390/molecules24050933
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发表时间：
2019-03-01
期刊：
影响因子：
4.6
通讯作者：
Jiang, Ling
中科院分区：
文献类型：
--
作者：
Zhou, Yuan;Huang, Liqun;Jiang, Ling
双组分系统（TCS）是细菌适应复杂多变环境的重要信号转导系统，近年来被认为是抗菌药物开发的新靶点。天然产物毛地黄黄酮（luteolin，Lut）能抑制海栖热袍菌（Thermotoga maritime）典型的组氨酸激酶（HK）HK 853的自磷酸化活性，但其抑制机制尚不清楚。在此，我们报告的结合机制的一个典型的黄酮与HK 853通过使用溶液NMR光谱，等温滴定量热法（ITC），和分子对接。我们发现毛地黄黄酮通过氢键和π-π堆积作用占据腺苷二磷酸（ADP）的结合口袋抑制HK 853的活性。我们的研究结果揭示了一个详细的机制，抑制黄酮和观察HK的构象和动力学变化。这些结果为从组氨酸激酶的角度设计抗菌剂提供了一种可行的方法。
The two-component system (TCS) is a significant signal transduction system for bacteria to adapt to complicated and variable environments, and thus has recently been regarded as a novel target for developing antibacterial agents. The natural product luteolin (Lut) can inhibit the autophosphorylation activity of the typical histidine kinase (HK) HK853 from Thermotoga maritime, but the inhibition mechanism is not known. Herein, we report on the binding mechanism of a typical flavone with HK853 by using solution NMR spectroscopy, isothermal titration calorimetry (ITC), and molecular docking. We show that luteolin inhibits the activity of HK853 by occupying the binding pocket of adenosine diphosphate (ADP) through hydrogen bonds and π-π stacking interaction structurally. Our results reveal a detailed mechanism for the inhibition of flavones and observe the conformational and dynamics changes of HK. These results should provide a feasible approach for antibacterial agent design from the view of the histidine kinases.