Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase
2020-07-23
发表期刊CELL
ISSN0092-8674
EISSN1097-4172
卷号182期号:2页码:417
发表状态已发表
DOI10.1016/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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