Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2-Reference-Cited by-全球学者库

Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2

Published:2022-04-05 Issue:16 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Zhao Yao¹²^ORCID,Zhu Yan¹²³^ORCID,Liu Xiang⁴⁵^ORCID,Jin Zhenming¹²^ORCID,Duan Yinkai¹²,Zhang Qi¹²^ORCID,Wu Chengyao¹²^ORCID,Feng Lu¹²^ORCID,Du Xiaoyu¹²,Zhao Jinyi¹²^ORCID,Shao Maolin¹²^ORCID,Zhang Bing¹²^ORCID,Yang Xiuna¹²^ORCID,Wu Lijie⁶^ORCID,Ji Xiaoyun⁷^ORCID,Guddat Luke W.⁸^ORCID,Yang Kailin⁹,Rao Zihe¹²⁴⁵¹⁰^ORCID,Yang Haitao¹²¹¹^ORCID

Affiliation:

1. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China

2. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China

3. University of Chinese Academy of Sciences, Beijing 100101, China

4. State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, Nankai University, Tianjin 300384, China

5. Tianjin Key Laboratory of Protein Sciences, Tianjin 300071, China

6. iHuman Institute, ShanghaiTech University, Shanghai 201210, China

7. The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China

8. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia

9. Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195

10. Laboratory of Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100091, China

11. Shanghai Clinical Research and Trial Center, Shanghai 201210, China

Abstract

Significance COVID-19 is a deadly rampaging infectious disease with over 480 million cases worldwide. Unfortunately, effective therapies remain very limited. Novel antiviral agents are urgently needed to combat this global healthcare crisis. Here, we elucidate the structural basis for replicase polyprotein cleavage and substrate specificity of SARS-CoV-2 main protease (M pro ). Through analyzing a series of high-resolution structures of SARS-CoV-2 M pro throughout the proteolytic process, we demonstrate the molecular mechanism of M pro in proteolytic processing that confers substrate specificity. Substrate selectivity is revealed using structures of the H41A mutant in complex with six individual native cleavage substrates. Our study underscores the mechanistic function of M pro in the viral life cycle, which provides structural insights to develop effective inhibitors against this essential target of SARS-CoV-2.

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2117142119

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