Structural highlights
Function
D2WXL6_9ALPC Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter.[ARBA:ARBA00002928] The papain-like proteinase 1 (PLP1) and papain-like proteinase 2 (PLP2) are responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PLP2 possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. PLP2 also antagonizes innate immune induction of type I interferon by blocking the nuclear translocation of host IRF-3.[ARBA:ARBA00025562]
Publication Abstract from PubMed
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(pro)), 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(pro) and can thermodynamically stabilize its folding. The structure of CCoV M(pro) in complex with GC376 was subsequently determined at 2.75 A. GC376 reacts with the catalytic residue C144 of CCoV M(pro) and forms an (R)- or (S)-configuration of hemithioacetal. A structural comparison of CCoV M(pro) and other animal CoV M(pro)s with SARS-CoV-2 M(pro) 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(pro)s, SARS-CoV-2 M(pro) 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 Furthermore, the conserved loop with residues 46-49 in animal coronaviral M(pro)s has been replaced by a stable alpha-helix in SARS-CoV-2 M(pro). In addition, the species-specific dimerization interface also influences the catalytic efficiency of CoV M(pro)s. Conclusively, the structural information of this study provides mechanistic insights into the ligand binding and dimerization of CoV M(pro)s among different species.
A Structural Comparison of SARS-CoV-2 Main Protease and Animal Coronaviral Main Protease Reveals Species-Specific Ligand Binding and Dimerization Mechanism.,Ho CY, Yu JX, Wang YC, Lin YC, Chiu YF, Gao JY, Lai SJ, Chen MJ, Huang WC, Tien N, Chen Y Int J Mol Sci. 2022 May 18;23(10):5669. doi: 10.3390/ijms23105669. PMID:35628479[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ho CY, Yu JX, Wang YC, Lin YC, Chiu YF, Gao JY, Lai SJ, Chen MJ, Huang WC, Tien N, Chen Y. A Structural Comparison of SARS-CoV-2 Main Protease and Animal Coronaviral Main Protease Reveals Species-Specific Ligand Binding and Dimerization Mechanism. Int J Mol Sci. 2022 May 18;23(10):5669. PMID:35628479 doi:10.3390/ijms23105669
