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Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase | |
Wang, Quan1,2; Wu, Jiqin3; Wang, Haofeng1,2,4; Gao, Yan5; Liu, Qiaojie3; Mu, An6,7; Ji, Wenxin6,7; Yan, Liming5; Zhu, Yan1,2; Zhu, Chen1,2; Fang, Xiang3,6; Yang, Xiaobao1,2; Huang, Yucen5; Gao, Hailong6,7; Liu, Fengjiang1,2; Ge, Ji5; Sun, Qianqian1,2; Yang, Xiuna1,2; Xu, Wenqing1,2; Liu, Zhijie1,2; Yang, Haitao1,2; Lou, Zhiyong5; Jiang, Biao1,2; Guddat, Luke W.8; Gong, Peng3; Rao, Zihe1,2,5,7
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2020-07-23 | |
发表期刊 | CELL |
ISSN | 0092-8674 |
EISSN | 1097-4172 |
卷号 | 182期号:2页码:417 |
发表状态 | 已发表 |
DOI | 10.1016/j.cell.2020.05.034 |
摘要 | Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Furthermore, we investigate the inhibition mechanism of the triphosphate metabolite of remdesivir through structural and kinetic analyses. A transition model from the nsp7-nsp8 hexadecameric primase complex to the nsp12-nsp7-nsp8 polymerase complex is also proposed to provide clues for the understanding of the coronavirus transcription and replication machinery. |
关键词 | 2019-nCoV SARS-CoV-2 COVID-19 Remdesivir Favipiravir Polymerase RdRP Virus nsp12 nsp8 |
收录类别 | SCI ; SCIE |
资助项目 | National Program on Key Research Project of China[2017YFC0840300][2020YFA0707500][2018YFA0507200] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB08020200] ; National Natural Science Foundation of China[81520108019][813300237][32041007] ; Science and Technology Commission of Shanghai Municipality, China[20431900200] |
WOS研究方向 | Biochemistry & Molecular Biology ; Cell Biology |
WOS类目 | Biochemistry & Molecular Biology ; Cell Biology |
WOS记录号 | WOS:000552745000013 |
出版者 | CELL PRESS |
WOS关键词 | SARS ; VISUALIZATION ; INSIGHTS ; GS-5734 ; COMPLEX ; EBOLA |
原始文献类型 | Article |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/121262 |
专题 | 免疫化学研究所_PI研究组_杨海涛组 免疫化学研究所_特聘教授组_抗体化学实验室 免疫化学研究所_特聘教授组_饶子和组 iHuman研究所_公共科研平台_生命科学电镜平台 iHuman研究所_PI研究组_刘志杰组 生命科学与技术学院_硕士生 生命科学与技术学院_博士生 生命科学与技术学院_PI研究组_许文青组 免疫化学研究所_PI研究组_王权组 |
共同第一作者 | Wu, Jiqin; Wang, Haofeng; Gao, Yan; Liu, Qiaojie |
通讯作者 | Wang, Quan; Gong, Peng; Rao, Zihe |
作者单位 | 1.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 3.Chinese Acad Sci, Ctr Biosafety Megasci, Wuhan Inst Virol, Key Lab Special Pathogens & Biosafety, 44 Xiao Hong Shan, Wuhan 430071, Hubei, Peoples R China 4.Tianjin Univ, Sch Life Sci, Tianjin, Peoples R China 5.Tsinghua Univ, Sch Life Sci & Sch Med, Lab Struct Biol, Beijing, Peoples R China 6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 7.Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, CAS Ctr Excellence Biomacromol, Beijing, Peoples R China 8.Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld, Australia |
第一作者单位 | 免疫化学研究所; 生命科学与技术学院 |
通讯作者单位 | 免疫化学研究所; 生命科学与技术学院 |
第一作者的第一单位 | 免疫化学研究所 |
推荐引用方式 GB/T 7714 | Wang, Quan,Wu, Jiqin,Wang, Haofeng,et al. Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase[J]. CELL,2020,182(2):417. |
APA | Wang, Quan.,Wu, Jiqin.,Wang, Haofeng.,Gao, Yan.,Liu, Qiaojie.,...&Rao, Zihe.(2020).Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase.CELL,182(2),417. |
MLA | Wang, Quan,et al."Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase".CELL 182.2(2020):417. |
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