Deactivation Pathway of Ras GTPase Underlies Conformational Substates as Targets for Drug Design
Deactivation Pathway of Ras GTPase Underlies Conformational Substates as Targets for Drug Design
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Ras GTPase 的失活途径是构象亚态作为药物设计目标的基础
DOI：
10.1021/acscatal.9b02556
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发表时间：
2019-08-01
期刊：
影响因子：
12.9
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
--
作者：
Lu, Shaoyong;Ni, Duan;Zhang, Jian
Ras GT3的异常激活与人类癌症密切相关。对Ras失活途径下构象转变的机制和结构见解为开发用于治疗Ras驱动的癌症的靶向疗法提供了机会。然而，通过原子分子动力学（MD）模拟完全捕获大规模构象转变仍然具有挑战性。在这里，我们进行了一个计算方案，结合了过渡途径生成算法，广泛的MD模拟，和马尔可夫状态模型分析，揭示的Ras失活途径的构象景观。我们的研究结果表明，Ras水解的逐步失活途径，并确定了几个关键的构象亚态沿着的失活途径。此外，我们发现了一个未探索的和潜在的变构结合位点的效应器结合区域的Ras的构象substates，这是进一步支持的定点穆塔。
Aberrant activation of Ras GTPase is closely associated with human cancers. Mechanistic and structural insights into conformational transitions underlying the Ras deactivation pathway provide opportunities for the development of targeted therapies for the treatment of Ras-driven cancers. It remains challenging, however, to completely capture a large-scale conformational transition by atomistic molecular dynamics (MD) simulations. Here, we carry out a computational scheme that combines a transition pathway generation algorithm, extensive MD simulations, and Markov state model analysis for disclosing the conformational landscape of the Ras deactivation pathway. Our findings suggest a stepwise deactivation pathway for Ras hydrolysis and identify several key conformational substates along the deactivation pathway. Furthermore, we discover an unexplored and potentially allosteric binding site on the effector-binding region of Ras in the conformational substates, which is further supported by site-directed muta...