MEK1及其突变体的曲美替尼结合轨迹马尔可夫模型分析
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1.吉林大学分子酶学工程教育部重点实验室

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基金项目:吉林省科技发展计划项目(3D5204381465)


Markov Model Analysis of Trametinib Binding Trajectory of MEK1 and Its Mutants
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1. Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education,School of Life Science,Jilin University

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    摘要:

    MEK1是Ras-Raf-MEK-ERK通路中重要的信号分子。在肿瘤发生中发挥着重要的作用。通路的Raf、MEK1等基因发生突变,导致通路被持续活化被认为是导致肿瘤无限增殖的重要原因之一。曲美替尼能有效的抑制MEK1的活性,MEK1结构中α螺旋的消失会降低曲美替尼的治疗效果。本实验通过PCCA+聚类分析、马尔可夫模型和通量分析等方法,对E203K突变体和曲美替尼的作用轨迹进行分析,研究发现E203K、P124S和野生型在与曲美替尼作用时,C166-S181部分靠近曲美替尼的一端都会发生解旋变为氢键转角,而远端结构变化有差异。

    Abstract:

    MEK1 is an important signaling molecule in the Ras-Raf-MEK-ERK pathway. It plays an important role in tumorigenesis. Mutation of Raf and MEK1 genes of the pathway, resulting in the pathway being continuously activated is believed to be one of the important causes of unlimited tumor proliferation. Trametinib can effectively inhibit the activity of MEK1, and the loss of alpha helix in MEK1 structure will reduce the therapeutic effect of trametinib. In this experiment, the trajectories of action of E203K mutant and trametinib were analyzed by PCCA+ clustering analysis, Markov model and flux analysis, and it was found that E203K, P124S and wild type all undergo deconvolution into hydrogen bonding corner at the end of C166-S181 part near trametinib when interacting with trametinib, while there are differences in structural changes at the distal end.

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刘明皓,李明昊,陈雪,韩葳葳. MEK1及其突变体的曲美替尼结合轨迹马尔可夫模型分析[J].生物医学工程学进展,2022,(4):223-229

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  • 收稿日期:2022-11-21
  • 最后修改日期:2022-12-29
  • 录用日期:2022-12-15
  • 在线发布日期: 2023-02-10
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