Conformational Features of Ras: Key Hydrogen-Bonding Interactions of Gln61 in the Intermediate State during GTP Hydrolysis.
Conformational Features of Ras: Key Hydrogen-Bonding Interactions of Gln61 in the Intermediate State during GTP Hydrolysis.
复制标题
Ras 的构象特征：Gln61 在 GTP 水解过程中中间态的关键氢键相互作用。
DOI：
10.1021/acs.jpcb.1c04679
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Xu,Xin
中科院分区：
文献类型：
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作者：
Zeng,Juan;Weng,Jingwei;Zhang,Yuwei;Xia,Fei;Cui,Qiang;Xu,Xin
RAS蛋白是抗击癌症最重要的药物靶点之一。为了有效地设计新的RAS药物，我们在这里通过广泛的复制交换分子动力学模拟表征了它的水解中间态RasGDPĚPi和产物态RasGDP的构象系综。RasGDPĚPi的几个亚态已经被确定，而结构分析揭示了一个未知的氢键网络，它稳定了水解中间态。更有趣的是，参与许多致癌突变的Gln61被发现参与了这个氢键网络，采用了一种特定的构象，与RasGTP状态相反，该构象总是指向PI。模拟还揭示了RasGDP具有多个亚态，这表明Ras与鸟核苷酸交换因子(GEF)之间的相互作用是一种构象选择机制。这些发现为RAS的药物设计提供了新的机会，通过稳定水解中间体或破坏其与GEF的相互作用。
The Ras protein is one of the most important drug targets for battling cancers. To effectively design novel drugs of Ras, we characterize here its conformational ensembles for the hydrolysis intermediate state RasGDPĚPi and the product state RasGDP by extensive replica-exchange molecular dynamics simulations. Several substates for RasGDPĚPi have been identified, while structural analyses have revealed an unrecognized hydrogen-bonding network that stabilizes the hydrolysis intermediate state. More interestingly, Gln61, which is involved in numerous oncogenic mutations, was found to be engaged in this hydrogen-bonding network, adopting a specific conformation that always points to Pi in contrast to that in the RasGTP state. The simulations also reveal that RasGDP has more than one substate, suggesting a conformational selection mechanism for the interaction between Ras and the guanine nucleotide exchange factors (GEFs). These findings offer new opportunities for the drug design of Ras by stabilizing the hydrolysis intermediate or disrupting its interaction with the GEFs.