Unveiling the "invisible" druggable conformations of GDP-bound inactive Ras
Unveiling the "invisible" druggable conformations of GDP-bound inactive Ras
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揭示 GDP 结合的非活性 Ras 的“隐形”可药物构象
DOI：
10.1073/pnas.2024725118
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发表时间：
2021-03-16
影响因子：
11.1
通讯作者：
Long, Dong
中科院分区：
文献类型：
--
作者：
Liu, Dan;Mao, Yunyun;Long, Dong
关于RAS是否可用药的流行观点在最近十年逐渐改变，因为发现了有效的抑制剂与天然结构中未见的神秘部位结合。尽管取得了很有希望的进展，但这些绑定口袋的难以捉摸的性质挑战了向更高效力和特异性发展的治疗学。在这里，我们通过将自旋弛豫验证的原子模拟与核磁共振化学位移和剩余偶极耦合结合起来，得到了鸟苷二磷酸(GDP)结合的非活性RAS的构象系综，这提供了可达微秒时间尺度的本征动力学的定量描述。通过实验获得信息的集合明确地证明了Ras.GDP中表面暴露和埋藏的隐蔽位点的预先形成，倡导通过靶向传统实验方法看不到的瞬时可药物构象来设计抑制。通过回顾测试RAS_GDP系综在虚拟筛选中从诱饵中识别已知配体的能力，建立了基于系综的理性设计的可行性。
The prevalent view on whether Ras is druggable has gradually changed in the recent decade with the discovery of effective inhibitors binding to cryptic sites unseen in the native structures. Despite the promising advances, therapeutics development toward higher potency and specificity is challenged by the elusive nature of these binding pockets. Here we derive a conformational ensemble of guanosine diphosphate (GDP)-bound inactive Ras by integrating spin relaxation-validated atomistic simulation with NMR chemical shifts and residual dipolar couplings, which provides a quantitative delineation of the intrinsic dynamics up to the microsecond timescale. The experimentally informed ensemble unequivocally demonstrates the preformation of both surface-exposed and buried cryptic sites in Ras.GDP, advocating design of inhibition by targeting the transient druggable conformers that are invisible to conventional experimental methods. The viability of the ensemble-based rational design has been established by retrospective testing of the ability of the Ras_GDP ensemble to identify known ligands from decoys in virtual screening.