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Cryo-EM Structure of an Extended SARS-CoV-2 Replication and Transcription Complex Reveals an Intermediate State in Cap Synthesis.
Yan, Liming; Ge, Ji; Zheng, Litao; Zhang, Ying; Gao, Yan; Wang, Tao; Huang, Yucen; Yang, Yunxiang; Gao, Shan; Li, Mingyu; Liu, Zhenyu; Wang, Haofeng; Li, Yingjian; Chen, Yu; Guddat, Luke W; Wang, Quan; Rao, Zihe; Lou, Zhiyong.
  • Yan L; MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China.
  • Ge J; School of Life Sciences, Tsinghua University, Beijing, China.
  • Zheng L; School of Life Sciences, Tsinghua University, Beijing, China.
  • Zhang Y; MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China.
  • Gao Y; MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Wang T; MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China.
  • Huang Y; MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China.
  • Yang Y; MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China.
  • Gao S; MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China.
  • Li M; MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China.
  • Liu Z; MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China.
  • Wang H; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Li Y; State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China.
  • Chen Y; State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China.
  • Guddat LW; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia.
  • Wang Q; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Rao Z; MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China; School of Life Sciences, Tsinghua University, Beijing, China; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China. El
  • Lou Z; MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China. Electronic address: louzy@mail.tsinghua.edu.cn.
Cell ; 184(1): 184-193.e10, 2021 01 07.
Article in English | MEDLINE | ID: covidwho-1385213
ABSTRACT
Transcription of SARS-CoV-2 mRNA requires sequential reactions facilitated by the replication and transcription complex (RTC). Here, we present a structural snapshot of SARS-CoV-2 RTC as it transitions toward cap structure synthesis. We determine the atomic cryo-EM structure of an extended RTC assembled by nsp7-nsp82-nsp12-nsp132-RNA and a single RNA-binding protein, nsp9. Nsp9 binds tightly to nsp12 (RdRp) NiRAN, allowing nsp9 N terminus inserting into the catalytic center of nsp12 NiRAN, which then inhibits activity. We also show that nsp12 NiRAN possesses guanylyltransferase activity, catalyzing the formation of cap core structure (GpppA). The orientation of nsp13 that anchors the 5' extension of template RNA shows a remarkable conformational shift, resulting in zinc finger 3 of its ZBD inserting into a minor groove of paired template-primer RNA. These results reason an intermediate state of RTC toward mRNA synthesis, pave a way to understand the RTC architecture, and provide a target for antiviral development.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: RNA, Messenger / RNA, Viral / Cryoelectron Microscopy / Coronavirus RNA-Dependent RNA Polymerase / Viral Replicase Complex Proteins / SARS-CoV-2 Language: English Journal: Cell Year: 2021 Document Type: Article Affiliation country: J.CELL.2020.11.016

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Full text: Available Collection: International databases Database: MEDLINE Main subject: RNA, Messenger / RNA, Viral / Cryoelectron Microscopy / Coronavirus RNA-Dependent RNA Polymerase / Viral Replicase Complex Proteins / SARS-CoV-2 Language: English Journal: Cell Year: 2021 Document Type: Article Affiliation country: J.CELL.2020.11.016