Identification of functional substates of KRas during GTP hydrolysis with enhanced sampling simulations.
Identification of functional substates of KRas during GTP hydrolysis with enhanced sampling simulations.
复制标题
通过增强的采样模拟在GTP水解过程中鉴定KRAS的功能取代。
DOI：
10.1039/d2cp00274d
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发表时间：
2022-03-30
期刊：
影响因子：
--
通讯作者：
Xu X
中科院分区：
文献类型：
--
作者：
Zeng J;Chen J;Xia F;Cui Q;Deng X;Xu X
作为主要信号传导途径的枢纽，Ras 蛋白由于其构象和/或催化特性的扰动而与 19% 的肿瘤引起的癌症有关。尽管进行了大量研究，但最重要的异构体 KRas 的构象亚状态的功能仍然难以捉摸。在这项工作中，我们对 GTP 水解循环期间各种化学状态下 KRas 的构象景观进行了广泛的模拟分析：反应物状态 KRasGTP·Mg2+、中间状态 KRasGDP·Pi·Mg2+ 和产物状态 KRasGDP·Mg2+。增强采样模拟的结果表明，KRasGTP·Mg2+的状态1在溶液中具有多种稳定的亚状态，其中之一可能是与GEF相互作用的原因。 KRasGTP·Mg2+的状态2具有两种亚状态“Tyr32in”和“Tyr32out”，它们分别准备与效应器和GAP相互作用。对于中间态 KRasGDP·Pi·Mg2+，Gln61 和 Pi 呈现出广泛的构象，这可能解释了与 HRas 和 NRas 中的情况相比，KRas 中 Gln61 突变的弱致癌作用。最后，产物态KRasGDP·Mg2+在溶液中具有两个以上的稳定亚态，这表明了与GEFs络合的构象选择机制。基于这些结果，讨论了 GTP 水解过程中针对 KRas 高能亚态结合位点的一些特定抑制策略。
As the hub of major signaling pathways, Ras proteins are implicated in 19% of tumor-caused cancers due to perturbations in their conformational and/or catalytic properties. Despite numerous studies, the functions of the conformational substates for the most important isoform, KRas, remain elusive. In this work, we perform an extensive simulation analysis on the conformational landscape of KRas in its various chemical states during the GTP hydrolysis cycle: the reactant state KRasGTP·Mg2+, the intermediate state KRasGDP·Pi·Mg2+ and the product state KRasGDP·Mg2+. The results from enhanced sampling simulations reveal that State 1 of KRasGTP·Mg2+ has multiple stable substates in solution, one of which might account for interacting with GEFs. State 2 of KRasGTP·Mg2+ features two substates “Tyr32in” and “Tyr32out”, which are poised to interact with effectors and GAPs, respectively. For the intermediate state KRasGDP·Pi·Mg2+, Gln61 and Pi are found to assume a broad set of conformations, which might account for the weak oncogenic effect of Gln61 mutations in KRas in contrast to the situation in HRas and NRas. Finally, the product state KRasGDP·Mg2+ has more than two stable substates in solution, pointing to a conformation-selection mechanism for complexation with GEFs. Based on these results, some specific inhibition strategies for targeting the binding sites of the high-energy substates of KRas during GTP hydrolysis are discussed.
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DOI：
10.1021/acs.jpcb.5b11110
发表时间：
2016-02-04
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Chakrabarti M;Jang H;Nussinov R
通讯作者：
Nussinov R
DOI：
10.1073/pnas.1812963116
发表时间：
2019-02-12
影响因子：
11.1
作者：
Hillig, Roman C.;Sautier, Brice;Bader, Benjamin
通讯作者：
Bader, Benjamin
影响因子：
4
作者：
Hobbs, G. Aaron;Der, Channing J.;Rossman, Kent L.
通讯作者：
Rossman, Kent L.
影响因子：
4.6
作者：
Dharmaiah, Srisathiyanarayanan;Tran, Timothy H.;Simanshu, Dhirendra K.
通讯作者：
Simanshu, Dhirendra K.
DOI：
10.1073/pnas.1404639111
发表时间：
2014-06-17
影响因子：
11.1
作者：
Hunter, John C.;Gurbani, Deepak;Westover, Kenneth D.
通讯作者：
Westover, Kenneth D.