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MOLECULAR DYNAMICS STUDY OF RADIOSENSITIVEMUTANT ALLELE OF PROTEIN KINASE ycdc28-srm G20SUSING hcdk2 AS MODEL

机译:用HCDK2作为模型蛋白激酶YCDC28-SRM G20S蛋白激酶YCDC28-SRM G20S的分子动力学研究

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The cyclin-dependent kinases play an essential role in the timingof cell division and repair, furthermore a high incidence of geneticalterations of CDKs or deregulation of CDK inhibitors have been observedin several cancers. These arguments make of CDC28 of Saccharomycescerevisiae yeast a very attractive model to study CDK regulationmechanisms. We observed certain gene mutations, including cdc28-srm[G20S], affect cell cycle progression, maintenance of different geneticstructures (Devin, 1990), checkpoint-control (Li, 1997) and increase cellradiosensitivity (Koltovaya, 1998). A cdc28-srm mutation is not atemperature-sensitive mutation and differs from known cdc28-ts mutations,since it shows the evident phenotypic manifestations at 30°C. The mutationis on the third glycine site in the conserved sequence GxGxxG of the G-richloop, whose position is opposite to the activation T-loop. Despite itsestablished importance, the role of the G-loop is still unclear. The crystalstructure of the human CDK2 served as model for the catalytic core of otherCDKs, including CDC28. Nanoseconds long molecular dynamicstrajectories of the CDK2/ATP complex were analysed. The MD simulationsof corresponded substitution CDK2-G16S in conserved G-loop shows thisamino acid importance and the induced conformational change in CDK2structure, resulting in the ATP removal from G-loop and in new aminoacids rearrangement in the T-loop.
机译:细胞周期蛋白依赖性激酶在细胞分裂和修复中发挥着重要作用,此外,在几种癌症中观察到CDK的Cdks或放松管病毒的基因或放松管制的高发生率。这些争论使酵母菌酵母的CDC28酵母是一种非常有吸引力的模型来研究CDK调控机制。我们观察到某些基因突变,包括CDC28-SRM [G20S],影响细胞周期进展,不同遗传结构的维持(Devin,1990),检查点控制(Li,1997)并增加Cellradiosensity(Koltovaya,1998)。 CDC28-SRM突变不是持久的敏感突变,并且与已知的CDC28-TS突变不同,因为它显示了30℃的明显表型表现。在G-richloop的保守序列GxGxxG中的第三甘氨酸位点上的致突变,其位置与激活T环相反。尽管其重要性很重要,但G圈的作用仍然不清楚。人CDK2的晶体结构用作其他支持的催化核的模型,包括CDC28。分析了CDK2 / ATP复合物的纳秒长分子动态性机械。在保守的G-Loop中对应的替代CDK2-G16S的MD模拟显示了该氨基酸的重要性和CDK2结构的诱导构象变化,从而从G环中取出ATP,并在T环中重新排列在新的氨基酸中。

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