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Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target

Yan Gao, View ORCID ProfileLiming Yan, Yucen Huang, Fengjiang Liu, Yao Zhao, Lin Cao, Tao Wang, Qianqian Sun, Zhenhua Ming, Lianqi Zhang, Ji Ge, Litao Zheng, Ying Zhang, Haofeng Wang, Yan Zhu, Chen Zhu, Tianyu Hu, Tian Hua, Bing Zhang, Xiuna Yang, Jun Li, Haitao Yang, Zhijie Liu, Wenqing Xu, Luke W. Guddat, View ORCID ProfileQuan Wang, View ORCID ProfileZhiyong Lou, View ORCID ProfileZihe Rao
doi: https://doi.org/10.1101/2020.03.16.993386
Yan Gao
1Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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Liming Yan
1Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China
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  • ORCID record for Liming Yan
Yucen Huang
1Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China
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Fengjiang Liu
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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Yao Zhao
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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Lin Cao
3State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin, China
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Tao Wang
1Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China
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Qianqian Sun
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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Zhenhua Ming
4State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Life Science and Technology, Guangxi University, Nanning, China
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Lianqi Zhang
1Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China
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Ji Ge
1Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China
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Litao Zheng
1Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China
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Ying Zhang
1Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China
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Haofeng Wang
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
5School of Life Sciences, Tianjin University, Tianjin, China
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Yan Zhu
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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Chen Zhu
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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Tianyu Hu
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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Tian Hua
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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Bing Zhang
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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Xiuna Yang
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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Jun Li
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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Haitao Yang
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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Zhijie Liu
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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Wenqing Xu
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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Luke W. Guddat
6School of Chemistry and Molecular Biosciences, the University of Queensland, Brisbane, Australia
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Quan Wang
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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  • ORCID record for Quan Wang
  • For correspondence: wangq@shanghaitech.edu.cn louzy@mail.tsinghua.edu.cn raozh@mail.tsinghua.edu.cn
Zhiyong Lou
1Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China
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  • For correspondence: wangq@shanghaitech.edu.cn louzy@mail.tsinghua.edu.cn raozh@mail.tsinghua.edu.cn
Zihe Rao
1Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China
2Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
3State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin, China
7National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing, China
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  • For correspondence: wangq@shanghaitech.edu.cn louzy@mail.tsinghua.edu.cn raozh@mail.tsinghua.edu.cn
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Abstract

A novel coronavirus (2019-nCoV) outbreak has caused a global pandemic resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase (RdRp, also named nsp12), which catalyzes the synthesis of viral RNA, is a key component of coronaviral replication/transcription machinery and appears to be a primary target for the antiviral drug, remdesivir. Here we report the cryo-EM structure of 2019-nCoV full-length nsp12 in complex with cofactors nsp7 and nsp8 at a resolution of 2.9-Å. Additional to the conserved architecture of the polymerase core of the viral polymerase family and a nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain featured in coronaviral RdRp, nsp12 possesses a newly identified β-hairpin domain at its N-terminal. Key residues for viral replication and transcription are observed. A comparative analysis to show how remdesivir binds to this polymerase is also provided. This structure provides insight into the central component of coronaviral replication/transcription machinery and sheds light on the design of new antiviral therapeutics targeting viral RdRp.

One Sentence Summary Structure of 2019-nCov RNA polymerase.

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Posted March 17, 2020.
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Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target
Yan Gao, Liming Yan, Yucen Huang, Fengjiang Liu, Yao Zhao, Lin Cao, Tao Wang, Qianqian Sun, Zhenhua Ming, Lianqi Zhang, Ji Ge, Litao Zheng, Ying Zhang, Haofeng Wang, Yan Zhu, Chen Zhu, Tianyu Hu, Tian Hua, Bing Zhang, Xiuna Yang, Jun Li, Haitao Yang, Zhijie Liu, Wenqing Xu, Luke W. Guddat, Quan Wang, Zhiyong Lou, Zihe Rao
bioRxiv 2020.03.16.993386; doi: https://doi.org/10.1101/2020.03.16.993386
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Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target
Yan Gao, Liming Yan, Yucen Huang, Fengjiang Liu, Yao Zhao, Lin Cao, Tao Wang, Qianqian Sun, Zhenhua Ming, Lianqi Zhang, Ji Ge, Litao Zheng, Ying Zhang, Haofeng Wang, Yan Zhu, Chen Zhu, Tianyu Hu, Tian Hua, Bing Zhang, Xiuna Yang, Jun Li, Haitao Yang, Zhijie Liu, Wenqing Xu, Luke W. Guddat, Quan Wang, Zhiyong Lou, Zihe Rao
bioRxiv 2020.03.16.993386; doi: https://doi.org/10.1101/2020.03.16.993386

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