当前位置: X-MOL 学术J. Mol. Graph. Model. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Molecular dynamics study of CDC25BR492L mutant causing the activity decrease of CDC25B
Journal of Molecular Graphics and Modelling ( IF 2.9 ) Pub Date : 2021-09-06 , DOI: 10.1016/j.jmgm.2021.108030
Hao-Xin Li 1 , Wen-Yu Yang 2 , Li-Peng Li 1 , Hui Zhou 1 , Wei-Ya Li 1 , Ying Ma 1 , Run-Ling Wang 1
Affiliation  

Cell division cycle 25B (CDC25B) was responsible for regulating the various stages of cell division in the cell cycle. R492L was one of the common types of CDC25B mutants. Researches showed that compared to CDC25BWT, CDC25BR492L mutant had a ∼100-fold reduction in the rate constant for forming phosphatase intermediate (k2). However, the molecular basis of how the CDC25BR492L mutant influenced the process of binding between CDC25B and CDK2/CyclinA was not yet known. Therefore, the optimizations of three-dimensional structure of the CDC25BWT-CDK2/CyclinA system and the CDC25BR492L-CDK2/CyclinA system were constructed by ZDOCK and RDOCK, and five methods were employed to verify the reasonability of the docking structure. Then the molecular dynamics simulations on the two systems were performed to explore the reason why CDC25BR492L mutant caused the weak interactions between CDC25BR492L and CDK2/CyclinA, respectively. The remote docking site (Arg488-Tyr497) and the second active site (Lys538-Arg544) of CDC25B were observed to have high fluctuations in the CDC25BR492L-CDK2/CyclinA system with post-analysis, where the high fluctuation of these two regions resulted in weak interactions between CD25B and CDK2. In addition, Asp38-Glu42 and Asp206-Asp210 of CDK2 showed the slightly descending fluctuation, and CDK2 revealed an enhanced the self-interaction, which made CDK2 keep a relatively stable state in the CDC25BR492L-CDK2/CyclinA system. Finally, Leu492 of CDC25B was speculated to be the key residue, which had great effects on the binding between CDC25BR492L and CDK2 in the CDC25BR492L-CDK2/CyclinA system. Consequently, overall analyses appeared in this study ultimately offered a helpful understanding of the weak interactions between CDC25BR492L and CDK2.



中文翻译:

CDC25BR492L突变体引起CDC25B活性降低的分子动力学研究

细胞分裂周期 25B (CDC25B) 负责调节细胞周期中细胞分裂的各个阶段。R492L 是 CDC25B 突变体的常见类型之一。研究表明,与 CDC25B WT相比,CDC25B R492L突变体形成磷酸酶中间体的速率常数 (k 2 )降低了约 100 倍。然而,CDC25B R492L突变体如何影响 CDC25B 和 CDK2/CyclinA 之间结合过程的分子基础尚不清楚。因此,CDC25B WT- CDK2/CyclinA系统和CDC25B R492L的三维结构优化-CDK2/CyclinA系统由ZDOCK和RDOCK构建,采用五种方法验证对接结构的合理性。然后对两个系统进行分子动力学模拟,以探讨CDC25B R492L突变体分别导致CDC25B R492L与CDK2/CyclinA之间弱相互作用的原因。观察到 CDC25B 的远程对接位点 (Arg488-Tyr497) 和第二个活性位点 (Lys538-Arg544) 在 CDC25B R492L 中有高波动-具有后分析的CDK2/CyclinA系统,其中这两个区域的高波动导致CD25B和CDK2之间的弱相互作用。此外,CDK2的Asp38-Glu42和Asp206-Asp210呈现小幅下降的波动,CDK2表现出增强的自相互作用,使CDK2在CDC25B R492L- CDK2/CyclinA系统中保持相对稳定的状态。最后推测CDC25B的Leu492是关键残基,对CDC25B R492L -CDK2/CyclinA系统中CDC25B R492L与CDK2的结合有很大影响。因此,本研究中出现的总体分析最终有助于了解 CDC25B R492L和 CDK2之间的弱相互作用。

更新日期:2021-09-09
down
wechat
bug