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An extended conformation of SARS-CoV-2 main protease reveals allosteric targets

文献类型：期刊论文

作者Sun, Zengchao3,4; Wang, Lu3; Li, Xiyang3; Fan, Chengpeng1; Xu, Jianfeng4; Shi, Zhenzhong4; Qiao, Huarui4; Lan, Zhongyun4; Zhang, Xin4; Li, Lingyun3
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2022-04-12
卷号119期号:15页码:9
关键词SARS-CoV-2 main protease nanobody M-pro extended conformation M-pro compact conformation
ISSN号0027-8424
DOI10.1073/pnas.2120913119
通讯作者Geng, Yong(gengyong@simm.ac.cn)
英文摘要The coronavirus main protease (M-pro) is required for viral replication and has enzymatical activity as a homodimer. Thus, targeting its dimerization is an effective strategy for developing allosteric inhibitors to suppress mutation escape. In this study, we obtained the extended conformation of the native monomer of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) M-pro by trapping it with nanobodies, and found that the catalytic domain and the helix domain dissociate, revealing allosteric targets. We also found another state, a compact conformation, similar to the dimeric form. Our data support that the M-pro may be in equilibrium among the monomeric extended conformation as the precursor of all other states, the compact conformation as the intermediate state, and the dimeric conformation as the active state. We designed an innovative Nanoluc Binary Technology (NanoBiT)-based high-throughput allosteric inhibitor assay based on the rearranged conformation. In addition, we identified a set of allosteric inhibitory nanobodies against M-pro, one of which is also a competitive inhibitor of M-pro. Our results provide insight into the maturation of the coronavirus M-pro and a way to develop anticoronaviral drugs through targeting the folding process to inhibit the autocleavage of the main protease.
WOS关键词CORONAVIRUS 3C-LIKE PROTEASE ; DIMER INTERFACE ; CRYSTAL-STRUCTURE ; SARS ; DOMAIN ; DIMERIZATION ; NANOBODIES ; MECHANISM ; CATALYSIS ; MUTATION
资助项目National Natural Science Foundation of China[31670743] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040326] ; Science and Technology Commission of Shanghai Municipality[18JC1415400] ; Joint Research Fund for Overseas, Hong Kong, and Macao Scholars[81628013] ; Natural Science Foundation of Shanghai[16ZR1442900] ; National Science Foundation for Young Scholar Projects[81803599] ; Zhejiang University Covid-19 Special Project[2020XGZX092] ; Shanghai Institute of Materia Medica, the Chinese Academy of Sciences[CASIMM0120164013] ; Shanghai Institute of Materia Medica, the Chinese Academy of Sciences[SIMM1606YZZ-06] ; Shanghai Institute of Materia Medica, the Chinese Academy of Sciences[SIMM1601KF-06] ; Shanghai Institute of Materia Medica, the Chinese Academy of Sciences[55201631121116101] ; Shanghai Institute of Materia Medica, the Chinese Academy of Sciences[55201631121108000] ; Shanghai Institute of Materia Medica, the Chinese Academy of Sciences[5112345601] ; Shanghai Institute of Materia Medica, the Chinese Academy of Sciences[2015123456005]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000789365800008
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/299376]  
专题新药研究国家重点实验室
通讯作者Geng, Yong
作者单位1.Wuhan Univ, Sch Basic Med Sci, Wuhan 430071, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Key Lab Receptor Res, Shanghai 201203, Peoples R China
4.Shanghai Ocean Univ, Coll Food Sci & Technol, Dept Biopharmaceut, Shanghai 201306, Peoples R China
推荐引用方式
GB/T 7714		 Sun, Zengchao,Wang, Lu,Li, Xiyang,et al. An extended conformation of SARS-CoV-2 main protease reveals allosteric targets[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2022,119(15):9.
APA Sun, Zengchao.,Wang, Lu.,Li, Xiyang.,Fan, Chengpeng.,Xu, Jianfeng.,...&Geng, Yong.(2022).An extended conformation of SARS-CoV-2 main protease reveals allosteric targets.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,119(15),9.
MLA Sun, Zengchao,et al."An extended conformation of SARS-CoV-2 main protease reveals allosteric targets".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 119.15(2022):9.

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来源：上海药物研究所

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