Cryo-EM structures of Lassa and Machupo virus polymerases complexed with cognate regulatory Z proteins identify targets for antivirals

doi:10.1038/s41564-021-00916-w

	Cryo-EM structures of Lassa and Machupo virus polymerases complexed with cognate regulatory Z proteins identify targets for antivirals
	Xu, Xin 1,2; Peng, Ruchao 2; Peng, Qi 2; Wang, Min 2; Xu, Ying 3; Liu, Sheng 2; Tian, Xiaolin 4; Deng, Haiteng 4; Tong, Yimin 5; Hu, Xiaoyou 1,5; Zhong, Jin1,5,6 ; Wang, Peiyi 7; Qi, Jianxun 2; Gao, George F.1,2,8; Shi, Yi 1,2,8,9,10
	2021
发表期刊	NATURE MICROBIOLOGY
ISSN	2058-5276
卷号	6 期号:7 页码:921-+
DOI	10.1038/s41564-021-00916-w
摘要	Zoonotic arenaviruses can lead to life-threating diseases in humans. These viruses encode a large (L) polymerase that transcribes and replicates the viral genome. At the late stage of replication, the multifunctional Z protein interacts with the L polymerase to shut down RNA synthesis and initiate virion assembly. However, the mechanism by which the Z protein regulates the activity of L polymerase is unclear. Here, we used cryo-electron microscopy to resolve the structures of both Lassa and Machupo virus L polymerases in complex with their cognate Z proteins, and viral RNA, to 3.1-3.9 angstrom resolutions. These structures reveal that Z protein binding induces conformational changes in two catalytic motifs of the L polymerase, and restrains their conformational dynamics to inhibit RNA synthesis, which is supported by hydrogen-deuterium exchange mass spectrometry analysis. Importantly, we show, by in vitro polymerase reactions, that Z proteins of Lassa and Machupo viruses can cross-inhibit their L polymerases, albeit with decreased inhibition efficiencies. This cross-reactivity results from a highly conserved determinant motif at the contacting interface, but is affected by other variable auxiliary motifs due to the divergent evolution of Old World and New World arenaviruses. These findings could provide promising targets for developing broad-spectrum antiviral drugs. Cryo-electron microscopy analyses show how Lassa and Machupo virus Z proteins bind the viral L polymerase and how this inhibits virus replication.
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收录类别	SCIE
语种	英语
WOS研究方向	Microbiology
WOS类目	Microbiology
WOS记录号	WOS:000661418100002
出版者	NATURE RESEARCH
原始文献类型	Article; Early Access
引用统计	被引频次：14[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/127568
专题	生命科学与技术学院_特聘教授组_钟劲组
通讯作者	Shi, Yi
作者单位	1.Univ Chinese Acad Sci, Savaid Med Sch, Beijing, Peoples R China; 2.Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, Beijing, Peoples R China; 3.Nanjing Agr Univ, Coll Life Sci, Nanjing, Peoples R China; 4.Tsinghua Univ, Sch Life Sci, MOE Key Lab Bioinformat, Beijing, Peoples R China; 5.Chinese Acad Sci, Inst Pasteur Shanghai, CAS Key Lab Mol Virol & Immunol, Shanghai, Peoples R China; 6.ShanghaiTech Univ, Shanghai, Peoples R China; 7.Southern Univ Sci & Technol, Dept Biol, Shenzhen, Peoples R China; 8.Chinese Acad Sci, Ctr Influenza Res & Early Warning CASCIRE, CAS TWAS Ctr Excellence Emerging Infect Dis CEEID, Beijing, Peoples R China; 9.Univ Chinese Acad Sci, Chongqing Gen Hosp, Chongqing Key Lab Neurodegenerat Dis, Chongqing, Peoples R China; 10.Jilin Univ, Coll Basic Med, Changchun, Peoples R China
推荐引用方式 GB/T 7714	Xu, Xin,Peng, Ruchao,Peng, Qi,et al. Cryo-EM structures of Lassa and Machupo virus polymerases complexed with cognate regulatory Z proteins identify targets for antivirals[J]. NATURE MICROBIOLOGY,2021,6(7):921-+.
APA	Xu, Xin.,Peng, Ruchao.,Peng, Qi.,Wang, Min.,Xu, Ying.,...&Shi, Yi.(2021).Cryo-EM structures of Lassa and Machupo virus polymerases complexed with cognate regulatory Z proteins identify targets for antivirals.NATURE MICROBIOLOGY,6(7),921-+.
MLA	Xu, Xin,et al."Cryo-EM structures of Lassa and Machupo virus polymerases complexed with cognate regulatory Z proteins identify targets for antivirals".NATURE MICROBIOLOGY 6.7(2021):921-+.