NMR-Derived Conformational Ensemble of State 1 of Activated Ras Reveals Insights into a Druggable Pocket
NMR-Derived Conformational Ensemble of State 1 of Activated Ras Reveals Insights into a Druggable Pocket
复制标题
核磁共振衍生的激活 Ras 状态 1 的构象整体揭示了对可药物口袋的见解。
DOI：
10.1021/acs.jpclett.0c00858
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发表时间：
2020-05-07
影响因子：
5.7
通讯作者：
Long, Dong
中科院分区：
文献类型：
--
作者：
Liu, Dan;Chen, Xiaomin;Long, Dong
Ras 基本构象中缺乏明显的口袋长期以来一直挑战着针对这种致癌蛋白的抑制剂的合理设计。另一方面，稀疏、瞬时形成的激活 Ras 状态 1 显示出明显的表面粗糙度，并且越来越多地被认为是药物发现的潜在目标。然而，状态1非常灵活，静态结构无法完全揭示其可用于药物设计的构象空间。在这里，我们提出了使用基于化学位移的建模导出的状态 1 的构象系综。该整体揭示了状态 1 下可成药口袋的内在可塑性，并展示了抑制剂识别的构象选择机制。该整体中的大量结构模板提供了热可访问口袋构象的全面描述，预计将极大地帮助抗 Ras 药物的合理设计。
Lack of apparent pockets in the ground conformation of Ras has long challenged the rational design of inhibitors against this oncogenic protein. The sparsely populated, transiently formed state 1 of activated Ras, on the other hand, shows appreciable surface roughness and is increasingly recognized as a potential target for drug discovery. The state 1, however, is extremely flexible, and a static structure cannot fully unveil its conformational space that can be exploited for drug design. Here, we present a conformational ensemble of state 1 that was derived using chemical shift-based modelling. The ensemble reveals the intrinsic plasticity of a druggable pocket in state 1 and demonstrates the mechanism of conformational selection for inhibitor recognition. The large set of structural templates in the ensemble, providing a comprehensive description of thermally accessible pocket conformations, are expected to significantly aid the rational design of anti-Ras drugs.