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DOI	10.1073/pnas.2024324118
	Role of bacterial RNA polymerase gate opening dynamics in DNA loading and antibiotics inhibition elucidated by quasi-Markov State Model
	Unarta I.C.; Cao S.; Kubo S.; Wang W.; Cheung P.P.-H.; Gao X.; Takada S.; Huang X.
发表日期	2021
ISSN	00278424
卷号	118 期号:17
英文摘要	To initiate transcription, the holoenzyme (RNA polymerase [RNAP] in complex with σ factor) loads the promoter DNA via the flexible loading gate created by the clamp and β-lobe, yet their roles in DNA loading have not been characterized. We used a quasi-Markov State Model (qMSM) built from extensive molecular dynamics simulations to elucidate the dynamics of Thermus aquaticus holoenzyme’s gate opening. We showed that during gate opening, β-lobe oscillates four orders of magnitude faster than the clamp, whose opening depends on the Switch 2’s structure. Myxopyronin, an antibiotic that binds to Switch 2, was shown to undergo a conformational selection mechanism to inhibit clamp opening. Importantly, we reveal a critical but undiscovered role of β-lobe, whose opening is sufficient for DNA loading even when the clamp is partially closed. These findings open the opportunity for the development of antibiotics targeting β-lobe of RNAP. Finally, we have shown that our qMSMs, which encode non-Markovian dynamics based on the generalized master equation formalism, hold great potential to be widely applied to study biomolecular dynamics. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Bacterial RNA polymerase; Markov State Model; Transcription initiation
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/179774
作者单位	Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Kowloon, Hong Kong; Center of Systems Biology and Human Health, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Kowloon, Hong Kong; Department of Chemistry, The Hong Kong University of Science and Technology, Kowloon, Hong Kong; Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, 606-8502, Japan; Computational Bioscience Research Center, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Saudi Arabia; Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Hong Kong, Hong Kong
推荐引用方式 GB/T 7714	Unarta I.C.,Cao S.,Kubo S.,et al. Role of bacterial RNA polymerase gate opening dynamics in DNA loading and antibiotics inhibition elucidated by quasi-Markov State Model[J],2021,118(17).
APA	Unarta I.C..,Cao S..,Kubo S..,Wang W..,Cheung P.P.-H..,...&Huang X..(2021).Role of bacterial RNA polymerase gate opening dynamics in DNA loading and antibiotics inhibition elucidated by quasi-Markov State Model.Proceedings of the National Academy of Sciences of the United States of America,118(17).
MLA	Unarta I.C.,et al."Role of bacterial RNA polymerase gate opening dynamics in DNA loading and antibiotics inhibition elucidated by quasi-Markov State Model".Proceedings of the National Academy of Sciences of the United States of America 118.17(2021).