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首页> 美国卫生研究院文献>other >Insight into the Intermolecular Recognition Mechanism between Keap1 and IKKβ Combining Homology Modelling Protein-Protein Docking Molecular Dynamics Simulations and Virtual Alanine Mutation
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Insight into the Intermolecular Recognition Mechanism between Keap1 and IKKβ Combining Homology Modelling Protein-Protein Docking Molecular Dynamics Simulations and Virtual Alanine Mutation

机译：结合同源性建模蛋白质-蛋白质对接分子动力学模拟和虚拟丙氨酸突变的研究了解Keap1和IKKβ之间的分子间识别机制。

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摘要

Degradation of certain proteins through the ubiquitin-proteasome pathway is a common strategy taken by the key modulators responsible for stress responses. Kelch-like ECH-associated protein-1(Keap1), a substrate adaptor component of the Cullin3 (Cul3)-based ubiquitin E3 ligase complex, mediates the ubiquitination of two key modulators, NF-E2-related factor 2 (Nrf2) and IκB kinase β (IKKβ), which are involved in the redox control of gene transcription. However, compared to the Keap1-Nrf2 protein-protein interaction (PPI), the intermolecular recognition mechanism of Keap1 and IKKβ has been poorly investigated. In order to explore the binding pattern between Keap1 and IKKβ, the PPI model of Keap1 and IKKβ was investigated. The structure of human IKKβ was constructed by means of the homology modeling method and using reported crystal structure of Xenopus laevis IKKβ as the template. A protein-protein docking method was applied to develop the Keap1-IKKβ complex model. After the refinement and visual analysis of docked proteins, the chosen pose was further optimized through molecular dynamics simulations. The resulting structure was utilized to conduct the virtual alanine mutation for the exploration of hot-spots significant for the intermolecular interaction. Overall, our results provided structural insights into the PPI model of Keap1-IKKβ and suggest that the substrate specificity of Keap1 depend on the interaction with the key tyrosines, namely Tyr525, Tyr574 and Tyr334. The study presented in the current project may be useful to design molecules that selectively modulate Keap1. The selective recognition mechanism of Keap1 with IKKβ or Nrf2 will be helpful to further know the crosstalk between NF-κB and Nrf2 signaling.
机译：通过泛素-蛋白酶体途径降解某些蛋白质是负责应激反应的关键调节剂采取的常见策略。基于Kullin3（Cul3）的泛素E3连接酶复合物的底物衔接子组件Kelch-like ECH相关蛋白1（Keap1）介导两个关键调节因子NF-E2相关因子2（Nrf2）和IκB的泛素化激酶β（IKKβ），参与基因转录的氧化还原控制。但是，与Keap1-Nrf2蛋白质-蛋白质相互作用（PPI）相比，对Keap1和IKKβ的分子间识别机制的研究很少。为了探索Keap1和IKKβ之间的结合模式，研究了Keap1和IKKβ的PPI模型。利用同源建模方法，以非洲爪蟾IKKβ的晶体结构为模板，构建人IKKβ的结构。蛋白质-蛋白质对接方法用于建立Keap1-IKKβ复杂模型。在对接蛋白进行细化和视觉分析之后，通过分子动力学模拟进一步优化了选择的位姿。利用所得结构进行虚拟丙氨酸突变，以探索对于分子间相互作用具有重要意义的热点。总体而言，我们的结果为Keap1-IKKβ的PPI模型提供了结构上的见解，并表明Keap1的底物特异性取决于与关键酪氨酸，即Tyr525，Tyr574和Tyr334的相互作用。当前项目中提出的研究可能对设计选择性调节Keap1的分子有用。 Keap1与IKKβ或Nrf2的选择性识别机制将有助于进一步了解NF-κB与Nrf2信号之间的串扰。

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