气候变化领域集成服务门户(CCPortal): Discovery of a hidden transient state in all bromodomain families

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DOI	10.1073/pnas.2017427118
	Discovery of a hidden transient state in all bromodomain families
	Raich L.; Meier K.; Günther J.; Christ C.D.; Noé F.; Olsson S.
发表日期	2021
ISSN	00278424
卷号	118 期号:4
英文摘要	Bromodomains (BDs) are small protein modules that interact with acetylated marks in histones. These posttranslational modifications are pivotal to regulate gene expression, making BDs promising targets to treat several diseases. While the general structure of BDs is well known, their dynamical features and their interplay with other macromolecules are poorly understood, hampering the rational design of potent and selective inhibitors. Here, we combine extensive molecular dynamics simulations, Markov state modeling, and available structural data to reveal a transiently formed state that is conserved across all BD families. It involves the breaking of two backbone hydrogen bonds that anchor the ZA-loop with the αA helix, opening a cryptic pocket that partially occludes the one associated to histone binding. By analyzing more than 1,900 experimental structures, we unveil just two adopting the hidden state, explaining why it has been previously unnoticed and providing direct structural evidence for its existence. Our results suggest that this state is an allosteric regulatory switch for BDs, potentially related to a recently unveiled BD-DNA–binding mode. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Allosteric effects; Bromodomains; Cryptic pockets; Markov models; Minor conformational states
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/180918
作者单位	Department of Mathematics and Computer Science, Freie Universität Berlin, Berlin, 14195, Germany; Computational Molecular Design, Pharmaceuticals, R&D, Bayer AG, Wuppertal, 42096, Germany; Computational Molecular Design, Pharmaceuticals, R&D, Bayer AG, Berlin, 13342, Germany; Department of Chemistry, Rice University, Houston, TX 77005, United States
推荐引用方式 GB/T 7714	Raich L.,Meier K.,Günther J.,et al. Discovery of a hidden transient state in all bromodomain families[J],2021,118(4).
APA	Raich L.,Meier K.,Günther J.,Christ C.D.,Noé F.,&Olsson S..(2021).Discovery of a hidden transient state in all bromodomain families.Proceedings of the National Academy of Sciences of the United States of America,118(4).
MLA	Raich L.,et al."Discovery of a hidden transient state in all bromodomain families".Proceedings of the National Academy of Sciences of the United States of America 118.4(2021).