Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center of Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China.
Graduate University of Chinese Academy of Science, Beijing 100049, China.
Molecules. 2019 Mar 7;24(5):933. doi: 10.3390/molecules24050933.
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 , 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.
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，因此最近被认为是开发抗菌药物的新靶点。天然产物木犀草素（Lut）可以抑制典型组氨酸激酶（HK）HK853 的自身磷酸化活性，但抑制机制尚不清楚。在此，我们通过溶液 NMR 光谱、等温滴定量热法（ITC）和分子对接报告了一种典型黄酮类化合物与 HK853 的结合机制。我们表明木犀草素通过氢键和π-π堆积相互作用占据二磷酸腺苷（ADP）的结合口袋来抑制 HK853 的活性。我们的结果揭示了黄酮类化合物抑制的详细机制，并观察到 HK 的构象和动力学变化。这些结果应该从组氨酸激酶的角度为抗菌药物设计提供一种可行的方法。
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