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The mechanism of inhibition of the cyclin-dependent kinase-2 as revealed by the molecular dynamics study on the complex CDK2 with the peptide substrate HHASPRK

机译:分子动力学研究揭示了具有肽底物HHASPRK的复合CDK2的抑制细胞周期蛋白依赖性激酶2的机制。

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摘要

Molecular dynamics (MD) simulations were used to explain structural details of cyclin-dependent kinase-2 (CDK2) inhibition by phosphorylation at T14 and/or Y15 located in the glycine-rich loop (G-loop). Ten-nanosecond-long simulations of fully active CDK2 in a complex with a short peptide (HHASPRK) substrate and of CDK2 inhibited by phosphorylation of T14 and/or Y15 were produced. The inhibitory phosphorylations at T14 and/or Y15 show namely an ATP misalignment and a G-loop shift (~5 Å) causing the opening of the substrate binding box. The biological functions of the G-loop and GxGxxG motif evolutionary conservation in protein kinases are discussed. The position of the ATP γ-phosphate relative to the phosphorylation site (S/T) of the peptide substrate in the active CDK2 is described and compared with inhibited forms of CDK2. The MD results clearly provide an explanation previously not known as to why a basic residue (R/K) is preferred at the P2 position in phosphorylated S/T peptide substrates.
机译:分子动力学(MD)模拟用于解释位于富含甘氨酸的环(G环)的T14和/或Y15处的磷酸化对细胞周期蛋白依赖性激酶2(CDK2)抑制的结构细节。产生了十纳秒长的完整活性CDK2在具有短肽(HHASPRK)底物的复合物中,以及被T14和/或Y15磷酸化抑制的CDK2的模拟。 T14和/或Y15处的抑制性磷酸化显示ATP错位和G环移位(〜5Å),导致底物结合盒打开。讨论了蛋白激酶中G环和GxGxxG基序进化保守的生物学功能。描述了ATPγ-磷酸相对于活性CDK2中肽底物的磷酸化位点(S / T)的位置,并将其与受抑制形式的CDK2进行了比较。 MD结果清楚地提供了以前未知的解释,说明为什么在磷酸化S / T肽底物的P2位上优选碱性残基(R / K)。

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