ArticleJournal of chemical information and modeling2024
Unexpected Single-Ligand Occupancy and Negative Cooperativity in the SARS-CoV-2 Main Protease.
Article in Journal of chemical information and modeling, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed.
- Decoding Enzyme-Inhibitor Kinetic Mechanisms by Isothermal Titration Calorimetry: The Case of SARS-CoV-2 3CLAnalytical chemistry · 2026Article
- Cooperativity and communication between the active sites of the dimeric SARS-CoV-2 main protease.Science advances · 2026Article
- Genomic Structural Equation Modeling Provides an Initial View of the Genetic Architecture Related to Type 1 Gaucher Disease.Human mutation · 2026Article
- Azapeptide-Based SARS-CoV-2 Main Protease Inhibitors: Design, Synthesis, Enzyme Inhibition, Structural Determination, and Antiviral Activity.Journal of medicinal chemistry · 2025Article
- Inhibition of dimeric SARS-CoV-2 Mpro displays positive cooperativity and a mixture of covalent and non-covalent binding.iScience · 2025Article
- Macromolecular crystallography at Elettra: current and future perspectives.Journal of synchrotron radiation · 2025Article
- Identifying Inhibitor-SARS-CoV2-3CLMolecules (Basel, Switzerland) · 2025Article
- The role of ATG16L1 in Crohn's disease and the structural alteration mechanisms and functional consequences of the rs2241880 variant.Frontiers in medicine · 2025Article
- Allostery in homodimeric SARS-CoV-2 main protease.Communications biology · 2024Article
- A comprehensive study of SARS-CoV-2 main protease (Mpro) inhibitor-resistant mutants selected in a VSV-based system.PLoS pathogens · 2024Article
- A comprehensive study of SARS-CoV-2 main protease (MbioRxiv : the preprint server for biology · 2023Article
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15 authors.
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Abstract
Many homodimeric enzymes tune their functions by exploiting either negative or positive cooperativity between subunits. In the SARS-CoV-2 Main protease (Mpro) homodimer, the latter has been suggested by symmetry in most of the 500 reported protease/ligand complex structures solved by macromolecular crystallography (MX). Here we apply the latter to both covalent and noncovalent ligands in complex with Mpro. Strikingly, our experiments show that the occupation of both active sites of the dimer originates from an excess of ligands. Indeed, cocrystals obtained using a 1:1 ligand/protomer stoichiometry lead to single occupation only. The empty binding site exhibits a catalytically inactive geometry in solution, as suggested by molecular dynamics simulations. Thus, Mpro operates through negative cooperativity with the asymmetric activity of the catalytic sites. This allows it to function with a wide range of substrate concentrations, making it resistant to saturation and potentially difficult to shut down, all properties advantageous for the virus' adaptability and resistance.
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