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A Structural Comparison of SARS-CoV-2 Main Protease and Animal Coronaviral Main Protease Reveals Species-Specific Ligand Binding and Dimerization Mechanism
oleh: Chien-Yi Ho, Jia-Xin Yu, Yu-Chuan Wang, Yu-Chuan Lin, Yi-Fang Chiu, Jing-Yan Gao, Shu-Jung Lai, Ming-Jen Chen, Wei-Chien Huang, Ni Tien, Yeh Chen
Format: | Article |
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Diterbitkan: | MDPI AG 2022-05-01 |
Deskripsi
Animal coronaviruses (CoVs) have been identified to be the origin of Severe Acute Respiratory Syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and probably SARS-CoV-2 that cause severe to fatal diseases in humans. Variations of zoonotic coronaviruses pose potential threats to global human beings. To overcome this problem, we focused on the main protease (M<sup>pro</sup>), which is an evolutionary conserved viral protein among different coronaviruses. The broad-spectrum anti-coronaviral drug, GC376, was repurposed to target canine coronavirus (CCoV), which causes gastrointestinal infections in dogs. We found that GC376 can efficiently block the protease activity of CCoV M<sup>pro</sup> and can thermodynamically stabilize its folding. The structure of CCoV M<sup>pro</sup> in complex with GC376 was subsequently determined at 2.75 Å. GC376 reacts with the catalytic residue C144 of CCoV M<sup>pro</sup> and forms an (R)- or (S)-configuration of hemithioacetal. A structural comparison of CCoV M<sup>pro</sup> and other animal CoV M<sup>pro</sup>s with SARS-CoV-2 M<sup>pro</sup> revealed three important structural determinants in a substrate-binding pocket that dictate entry and release of substrates. As compared with the conserved A141 of the S1 site and P188 of the S4 site in animal coronaviral M<sup>pro</sup>s, SARS-CoV-2 M<sup>pro</sup> contains N142 and Q189 at equivalent positions which are considered to be more catalytically compatible. Furthermore, the conserved loop with residues 46–49 in animal coronaviral M<sup>pro</sup>s has been replaced by a stable α-helix in SARS-CoV-2 M<sup>pro</sup>. In addition, the species-specific dimerization interface also influences the catalytic efficiency of CoV M<sup>pro</sup>s. Conclusively, the structural information of this study provides mechanistic insights into the ligand binding and dimerization of CoV M<sup>pro</sup>s among different species.