ArticleThe Journal of biological chemistry2022
Key dimer interface residues impact the catalytic activity of 3CLpro, the main protease of SARS-CoV-2.
Article in The Journal of biological chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 63 citations in OpenAlex.
- The C117D oxidation mimic reveals the monomeric structure of SARS-CoV-2 main protease.Protein science : a publication of the Protein Society · 2026Article
- Super-resolution atlas of SARS-CoV-2 infection reveals protease-dependent organelle maturation, dsRNA landscapes, and intracellular structural proteins.Nature communications · 2026Article
- Article
- Linking biochemical and cellular efficacy of MERS coronavirus main protease inhibitors.ACS pharmacology & translational science · 2026Article
- SARS-CoV-2 3CL protease interaction with host factors - identifying novel drug targets.Archives of virology · 2026Review
- Multicyclic D-Stereospecific Hydrolase Dimer With High Sustained Activity.Angewandte Chemie (International ed. in English) · 2026Article
- Statistical crystallography reveals an allosteric network in SARS-CoV-2 MCommunications biology · 2026Article
- Linking biochemical and cellular efficacy of MERS coronavirus main protease inhibitors.bioRxiv : the preprint server for biology · 2026Article
- MarinePharmaceuticals (Basel, Switzerland) · 2026Article
- Cooperativity and communication between the active sites of the dimeric SARS-CoV-2 main protease.Science advances · 2026Article
- Residues of the ribose binding site are required for human ribokinase activity.Journal of structural biology: X · 2025Article
- Inhibitor-induced dimerization mediates lufotrelvir resistance in mutants of SARS-CoV-2 3C-like protease.Protein science : a publication of the Protein Society · 2025Article
- Enzyme kinetics model for the coronavirus main protease including dimerization and ligand binding.Biophysical journal · 2025Article
- Strategy to overcome a nirmatrelvir resistance mechanism in the SARS-CoV-2 nsp5 protease.Science advances · 2025Article
- Unveiling the mechanism of action of a novel natural dual inhibitor of SARS-CoV-2 Mpro and PLpro with molecular dynamics simulations.Natural products and bioprospecting · 2025Article
- Development of small molecule non-covalent coronavirus 3CL protease inhibitors from DNA-encoded chemical library screening.Nature communications · 2025Article
- Revealing SARS-CoV-2 MComputational and structural biotechnology journal · 2024Article
- Computational Insights into Acrylamide Fragment Inhibition of SARS-CoV-2 Main Protease.Current issues in molecular biology · 2024Article
- Allostery in homodimeric SARS-CoV-2 main protease.Communications biology · 2024Article
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3 authors at 1 institution in 1 country.
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Abstract
3C-like protease (3CLpro) processes and liberates functional viral proteins essential for the maturation and infectivity of severe acute respiratory syndrome coronavirus 2, the virus responsible for COVID-19. It has been suggested that 3CLpro is catalytically active as a dimer, making the dimerization interface a target for antiviral development. Guided by structural analysis, here we introduced single amino acid substitutions at nine residues at three key sites of the dimer interface to assess their impact on dimerization and activity. We show that at site 1, alanine substitution of S1 or E166 increased by twofold or reduced relative activity, respectively. At site 2, alanine substitution of S10 or E14 eliminated activity, whereas K12A exhibited ∼60% relative activity. At site 3, alanine substitution of R4, E290, or Q299 eliminated activity, whereas S139A exhibited 46% relative activity. We further found that the oligomerization states of the dimer interface mutants varied; the inactive mutants R4A, R4Q, S10A/C, E14A/D/Q/S, E290A, and Q299A/E were present as dimers, demonstrating that dimerization is not an indication of catalytically active 3CLpro. In addition, present mostly as monomers, K12A displayed residual activity, which could be attributed to the conspicuous amount of dimer present. Finally, differential scanning calorimetry did not reveal a direct relationship between the thermodynamic stability of mutants with oligomerization or catalytic activity. These results provide insights on two allosteric sites, R4/E290 and S10/E14, that may promote the design of antiviral compounds that target the dimer interface rather than the active site of severe acute respiratory syndrome coronavirus 2 3CLpro.
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