Open AccessStructural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2
Author(s) -
Yao Zhao,
Yan Zhu,
Xiang Liu,
Zhixing Jin,
Ying Duan,
Qi Zhang,
Chengyao Wu,
Feng Lu,
Xiaoyu Du,
Jinyi Zhao,
Maolin Shao,
Bing Zhang,
Xiuna Yang,
Lei Wu,
Xiaoyun Ji,
L.W. Guddat,
Kailin Yang,
Zihe Rao,
Haitao Yang
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2117142119
Subject(s) - protease , rna dependent rna polymerase , cleavage (geology) , virology , covid-19 , biology , chemistry , computational biology , biochemistry , enzyme , medicine , polymerase , paleontology , disease , pathology , fracture (geology) , infectious disease (medical specialty)
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 (Mpro ). Through analyzing a series of high-resolution structures of SARS-CoV-2 Mpro throughout the proteolytic process, we demonstrate the molecular mechanism of Mpro 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 Mpro in the viral life cycle, which provides structural insights to develop effective inhibitors against this essential target of SARS-CoV-2.