7XJW

Crystal structure of canine coronavirus main protease in complex with GC376

Summary for 7XJW

• Entry DOI: 10.2210/pdb7xjw/pdb
• Descriptor: ORF1a polyprotein, (1S,2S)-2-({N-[(benzyloxy)carbonyl]-L-leucyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid (3 entities in total)
• Functional Keywords: 3c-like proteinase, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Canine coronavirus
• Total number of polymer chains: 8
• Total formula weight: 268471.82

Authors

Wang, Y.C.,Yang, C.S.,Hou, M.H.,Tsai, C.L.,Chiu, Y.F.,Chen, Y. (deposition date: 2022-04-18, release date: 2023-05-31, Last modification date: 2024-11-06)

Primary citation

Ho, C.Y.,Yu, J.X.,Wang, Y.C.,Lin, Y.C.,Chiu, Y.F.,Gao, J.Y.,Lai, S.J.,Chen, M.J.,Huang, W.C.,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, 23:-, 2022

PubMed Abstract: 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), 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 and can thermodynamically stabilize its folding. The structure of CCoV M in complex with GC376 was subsequently determined at 2.75 Å. GC376 reacts with the catalytic residue C144 of CCoV M and forms an (R)- or (S)-configuration of hemithioacetal. A structural comparison of CCoV M and other animal CoV Ms with SARS-CoV-2 M 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 Ms, SARS-CoV-2 M 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 Furthermore, the conserved loop with residues 46-49 in animal coronaviral Ms has been replaced by a stable α-helix in SARS-CoV-2 M. In addition, the species-specific dimerization interface also influences the catalytic efficiency of CoV Ms. Conclusively, the structural information of this study provides mechanistic insights into the ligand binding and dimerization of CoV Ms among different species.

PubMed: 35628479
DOI: 10.3390/ijms23105669

Experimental method

X-RAY DIFFRACTION (2.75 Å)