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Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase.
Wang, Quan; Wu, Jiqin; Wang, Haofeng; Gao, Yan; Liu, Qiaojie; Mu, An; Ji, Wenxin; Yan, Liming; Zhu, Yan; Zhu, Chen; Fang, Xiang; Yang, Xiaobao; Huang, Yucen; Gao, Hailong; Liu, Fengjiang; Ge, Ji; Sun, Qianqian; Yang, Xiuna; Xu, Wenqing; Liu, Zhijie; Yang, Haitao; Lou, Zhiyong; Jiang, Biao; Guddat, Luke W; Gong, Peng; Rao, Zihe.
  • Wang Q; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China. Electronic address: wangq@shanghaitech.edu.cn.
  • Wu J; Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.44 Xiao Hong Shan, Wuhan, Hubei, 430071, China.
  • Wang H; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China; School of Life Sciences, Tianjin University, Tianjin, China.
  • Gao Y; Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China.
  • Liu Q; Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.44 Xiao Hong Shan, Wuhan, Hubei, 430071, China.
  • Mu A; University of Chinese Academy of Sciences, Beijing, 100049, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing, China.
  • Ji W; University of Chinese Academy of Sciences, Beijing, 100049, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing, China.
  • Yan L; Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China.
  • Zhu Y; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Zhu C; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Fang X; Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.44 Xiao Hong Shan, Wuhan, Hubei, 430071, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • Yang X; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Huang Y; Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China.
  • Gao H; University of Chinese Academy of Sciences, Beijing, 100049, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing, China.
  • Liu F; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Ge J; Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China.
  • Sun Q; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Yang X; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Xu W; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Liu Z; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Yang H; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Lou Z; Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China.
  • Jiang B; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Guddat LW; School of Chemistry and Molecular Biosciences, the University of Queensland, Brisbane, Australia.
  • Gong P; Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No.44 Xiao Hong Shan, Wuhan, Hubei, 430071, China. Electronic address: gongpeng@wh.iov.cn.
  • Rao Z; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China; National Laboratory of Biomacromolecules,
Cell ; 182(2): 417-428.e13, 2020 07 23.
Article in English | MEDLINE | ID: covidwho-342735
Semantic information from SemMedBD (by NLM)
1. Polymerase PART_OF 2019 novel coronavirus
Subject
Polymerase
Predicate
PART_OF
Object
2019 novel coronavirus
2. favipiravir TREATS COVID-19
Subject
favipiravir
Predicate
TREATS
Object
COVID-19
3. remdesivir TREATS COVID-19
Subject
remdesivir
Predicate
TREATS
Object
COVID-19
4. Nucleic Acids compared_with Oligonucleotide Primers
Subject
Nucleic Acids
Predicate
compared_with
Object
Oligonucleotide Primers
5. Polymerase PART_OF 2019 novel coronavirus
Subject
Polymerase
Predicate
PART_OF
Object
2019 novel coronavirus
6. favipiravir TREATS COVID-19
Subject
favipiravir
Predicate
TREATS
Object
COVID-19
7. remdesivir TREATS COVID-19
Subject
remdesivir
Predicate
TREATS
Object
COVID-19
8. Nucleic Acids compared_with Oligonucleotide Primers
Subject
Nucleic Acids
Predicate
compared_with
Object
Oligonucleotide Primers
ABSTRACT
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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: RNA-Dependent RNA Polymerase / Viral Nonstructural Proteins / Betacoronavirus Type of study: Prognostic study Language: English Journal: Cell Year: 2020 Document Type: Article

Full text: Available Collection: International databases Database: MEDLINE Main subject: RNA-Dependent RNA Polymerase / Viral Nonstructural Proteins / Betacoronavirus Type of study: Prognostic study Language: English Journal: Cell Year: 2020 Document Type: Article