气候变化领域集成服务门户(CCPortal): Unveiling the "invisible" druggable conformations of GDP-bound inactive Ras

CCPortal

DOI	10.1073/pnas.2024725118
	Unveiling the "invisible" druggable conformations of GDP-bound inactive Ras
	Liu D.; Mao Y.; Gu X.; Zhou Y.; Long D.
发表日期	2021
ISSN	00278424
卷号	118 期号:11
英文摘要	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 surfaceexposed 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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Chemical shift; Conformational ensemble; Residual dipolar coupling; Spin relaxation; Virtual screening
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180230
作者单位	Hefei National Laboratory for Physical Sciences at the Microscale, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China; Department of Chemistry, University of Science and Technology of China, Hefei, 230026, China
推荐引用方式 GB/T 7714	Liu D.,Mao Y.,Gu X.,et al. Unveiling the "invisible" druggable conformations of GDP-bound inactive Ras[J],2021,118(11).
APA	Liu D.,Mao Y.,Gu X.,Zhou Y.,&Long D..(2021).Unveiling the "invisible" druggable conformations of GDP-bound inactive Ras.Proceedings of the National Academy of Sciences of the United States of America,118(11).
MLA	Liu D.,et al."Unveiling the "invisible" druggable conformations of GDP-bound inactive Ras".Proceedings of the National Academy of Sciences of the United States of America 118.11(2021).