Deactivation Pathway of Ras GTPase Underlies Conformational Substates as Targets for Drug Design,ACS Catalysis

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Deactivation Pathway of Ras GTPase Underlies Conformational Substates as Targets for Drug Design
ACS Catalysis ( IF 11.3 ) Pub Date : 2019-07-09 00:00:00 , DOI: 10.1021/acscatal.9b02556
Shaoyong Lu ₁ , Duan Ni ₁ , Chengxiang Wang ₁ , Xinheng He ₁ , Houwen Lin ₂ , Zheng Wang ₃ , Jian Zhang ₁

Affiliation

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 mutagenesis experiments. This site could be exploited to the design of Ras inhibitors to block Ras–effector interactions.

中文翻译：

Ras GTPase的失活途径以构象亚状态为药物设计目标

Ras GTPase的异常激活与人类癌症密切相关。对Ras失活途径基础的构象转变的机械和结构见解为开发靶向治疗Ras驱动的癌症的靶向疗法提供了机会。但是，通过原子分子动力学（MD）模拟完全捕获大规模的构象转变仍然具有挑战性。在这里，我们执行了一个计算方案，该方案结合了转换途径生成算法，广泛的MD模拟和Markov状态模型分析，以揭示Ras失活途径的构象态势。我们的研究结果表明Ras水解的逐步失活途径，并确定沿失活途径的几个关键构象亚状态。此外，我们在构象亚状态的Ras的效应子结合区域上发现了一个未探索的和潜在的变构结合位点，这进一步得到了定点诱变实验的支持。该位点可用于设计Ras抑制剂来阻断Ras与效应子的相互作用。

更新日期：2019-07-09

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