MEK1及其突变体的曲美替尼结合轨迹的马尔可夫模型分析  

Markov Model Analysis of Trametinib Binding Trajectory of MEK1 and Its Mutants

作　　者：刘明皓 李明昊 陈雪 韩葳葳 LIU Minghao;LI Minghao;CHEN Xue;HAN Weiwei(Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education,School of Life Science,Jilin University,Changchun,Jilin 130012,China)

机构地区：[1]吉林大学分子酶学工程教育部重点实验室,吉林大学生命科学学院,吉林长春130012

出　　处：《生物医学工程学进展》2022年第4期223-229,共7页Progress in Biomedical Engineering

基　　金：吉林省科技发展计划项目(3D5204381465)。

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。通路中的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。曲美替尼能有效地抑制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。该研究通过PCCA+聚类算法、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MEK1在与曲美替尼作用时,C166-S181部分靠近曲美替尼的一端会发生解旋变为氢键转角,而远端螺旋则不会发生解旋。MEK1 is an important signal 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 algorithm,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.

关 键 词：丝裂原活化蛋白激酶激酶1 曲美替尼 E203K突变体 马尔可夫模型 通量分析 

分 类 号：Q6[生物学—生物物理学]