ArticleThe Journal of biological chemistry2015
Ligand-induced Dimerization of Middle East Respiratory Syndrome (MERS) Coronavirus nsp5 Protease (3CLpro): IMPLICATIONS FOR nsp5 REGULATION AND THE DEVELOPMENT OF ANTIVIRALS.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 105 papers.
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Who cites it
105 citing papers in PubMed.
- Computational Discovery of MERS-CoV Main Protease Inhibitors Through Screening and Molecular Dynamics Simulations.Proteins · 2026Article
- Article
- Linking biochemical and cellular efficacy of MERS coronavirus main protease inhibitors.ACS pharmacology & translational science · 2026Article
- Linking biochemical and cellular efficacy of MERS coronavirus main protease inhibitors.bioRxiv : the preprint server for biology · 2026Article
- Cooperativity and communication between the active sites of the dimeric SARS-CoV-2 main protease.Science advances · 2026Article
- A structural roadmap for the formation of the coronavirus nsp3/nsp4 double membrane vesicle pore and its implications for polyprotein processing and replication/transcription.Journal of virology · 2025Article
- Discovery of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 Main Protease through Computer-Aided Drug Design.Journal of medicinal chemistry · 2025Article
- Azapeptide-Based SARS-CoV-2 Main Protease Inhibitors: Design, Synthesis, Enzyme Inhibition, Structural Determination, and Antiviral Activity.Journal of medicinal chemistry · 2025Article
- A luminescent attenuated SARS-CoV-2 for the identification and validation of drug-resistant mutants.Journal of virology · 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
- Inhibition of dimeric SARS-CoV-2 Mpro displays positive cooperativity and a mixture of covalent and non-covalent binding.iScience · 2025Article
- Dihydropyrimidine-2-thione derivatives as SARS-CoV-2 main protease inhibitors: synthesis, SAR andRSC advances · 2025Article
- Identification of Potent, Broad-Spectrum Coronavirus Main Protease Inhibitors for Pandemic Preparedness.Journal of medicinal chemistry · 2024Article
- Novel Pan-Coronavirus 3CL Protease Inhibitor MK-7845: Biological and Pharmacological Profiling.Viruses · 2024Article
- NSP6 inhibits the production of ACE2-containing exosomes to promote SARS-CoV-2 infectivity.mBio · 2024Article
- On Inactivation of the Coronavirus Main Protease.Journal of chemical information and modeling · 2024Article
- AnHeliyon · 2024Article
- Porcine deltacoronavirus nsp5 antagonizes type I interferon signaling by cleaving IFIT3.Journal of virology · 2024Article
- Review
45 more citing papers are in PubMed but not listed here.
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9 authors.
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Abstract
All coronaviruses, including the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV) from the β-CoV subgroup, require the proteolytic activity of the nsp5 protease (also known as 3C-like protease, 3CL(pro)) during virus replication, making it a high value target for the development of anti-coronavirus therapeutics. Kinetic studies indicate that in contrast to 3CL(pro) from other β-CoV 2c members, including HKU4 and HKU5, MERS-CoV 3CL(pro) is less efficient at processing a peptide substrate due to MERS-CoV 3CL(pro) being a weakly associated dimer. Conversely, HKU4, HKU5, and SARS-CoV 3CL(pro) enzymes are tightly associated dimers. Analytical ultracentrifugation studies support that MERS-CoV 3CL(pro) is a weakly associated dimer (Kd ∼52 μm) with a slow off-rate. Peptidomimetic inhibitors of MERS-CoV 3CL(pro) were synthesized and utilized in analytical ultracentrifugation experiments and demonstrate that MERS-CoV 3CL(pro) undergoes significant ligand-induced dimerization. Kinetic studies also revealed that designed reversible inhibitors act as activators at a low compound concentration as a result of induced dimerization. Primary sequence comparisons and x-ray structural analyses of two MERS-CoV 3CLpro and inhibitor complexes, determined to 1.6 Å, reveal remarkable structural similarity of the dimer interface with 3CL(pro) from HKU4-CoV and HKU5-CoV. Despite this structural similarity, substantial differences in the dimerization ability suggest that long range interactions by the nonconserved amino acids distant from the dimer interface may control MERS-CoV 3CL(pro) dimerization. Activation of MERS-CoV 3CL(pro) through ligand-induced dimerization appears to be unique within the genogroup 2c and may potentially increase the complexity in the development of MERS-CoV 3CL(pro) inhibitors as antiviral agents.
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