ArticlePLoS computational biology2011
Dynamically-driven inactivation of the catalytic machinery of the SARS 3C-like protease by the N214A mutation on the extra domain.
Article in PLoS computational biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24 citing papers in PubMed.
- Statistical crystallography reveals an allosteric network in SARS-CoV-2 MCommunications biology · 2026Article
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- Allosteric Hotspots in the Main Protease of SARS-CoV-2.Journal of molecular biology · 2022Article
- A review of the effects of ATP and hydroxychloroquine on the phase separation of the SARS-CoV-2 nucleocapsid protein.Biophysical reviews · 2022Review
- CTD of SARS-CoV-2 N protein is a cryptic domain for binding ATP and nucleic acid that interplay in modulating phase separation.Protein science : a publication of the Protein Society · 2022Article
- Myricetin Allosterically Inhibits the Dengue NS2B-NS3 Protease by Disrupting the Active and Locking the Inactive Conformations.ACS omega · 2022Article
- Tethering-induced destabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1.Scientific reports · 2021Article
- Structural basis of anti-SARS-CoV-2 activity of HCQ: specific binding to N protein to disrupt its interaction with nucleic acids and LLPS.QRB discovery · 2021Article
- Computational analysis of dynamic allostery and control in the SARS-CoV-2 main protease.Journal of the Royal Society, Interface · 2021Article
- Screening and evaluation of approved drugs as inhibitors of main protease of SARS-CoV-2.International journal of biological macromolecules · 2020Article
- Curcumin Allosterically Inhibits the Dengue NS2B-NS3 Protease by Disrupting Its Active Conformation.ACS omega · 2020Article
- Structurally- and dynamically-driven allostery of the chymotrypsin-like proteases of SARS, Dengue and Zika viruses.Progress in biophysics and molecular biology · 2019Review
- Solution conformations of Zika NS2B-NS3pro and its inhibition by natural products from edible plants.PloS one · 2017Article
- Conformational Flexibility of a Short Loop near the Active Site of the SARS-3CLpro is Essential to Maintain Catalytic Activity.Scientific reports · 2016Article
- Ligand-induced Dimerization of Middle East Respiratory Syndrome (MERS) Coronavirus nsp5 Protease (3CLpro): IMPLICATIONS FOR nsp5 REGULATION AND THE DEVELOPMENT OF ANTIVIRALS.The Journal of biological chemistry · 2015Article
- Structures of the Middle East respiratory syndrome coronavirus 3C-like protease reveal insights into substrate specificity.Acta crystallographica. Section D, Biological crystallography · 2015Article
- Article
- Article
- Why do proteins aggregate? "Intrinsically insoluble proteins" and "dark mediators" revealed by studies on "insoluble proteins" solubilized in pure water.F1000Research · 2013Review
- Structured crowding and its effects on enzyme catalysis.Topics in current chemistry · 2013Review
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8 authors.
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Abstract
Despite utilizing the same chymotrypsin fold to host the catalytic machinery, coronavirus 3C-like proteases (3CLpro) noticeably differ from picornavirus 3C proteases in acquiring an extra helical domain in evolution. Previously, the extra domain was demonstrated to regulate the catalysis of the SARS-CoV 3CLpro by controlling its dimerization. Here, we studied N214A, another mutant with only a doubled dissociation constant but significantly abolished activity. Unexpectedly, N214A still adopts the dimeric structure almost identical to that of the wild-type (WT) enzyme. Thus, we conducted 30-ns molecular dynamics (MD) simulations for N214A, WT, and R298A which we previously characterized to be a monomer with the collapsed catalytic machinery. Remarkably, three proteases display distinctive dynamical behaviors. While in WT, the catalytic machinery stably retains in the activated state; in R298A it remains largely collapsed in the inactivated state, thus implying that two states are not only structurally very distinguishable but also dynamically well separated. Surprisingly, in N214A the catalytic dyad becomes dynamically unstable and many residues constituting the catalytic machinery jump to sample the conformations highly resembling those of R298A. Therefore, the N214A mutation appears to trigger the dramatic change of the enzyme dynamics in the context of the dimeric form which ultimately inactivates the catalytic machinery. The present MD simulations represent the longest reported so far for the SARS-CoV 3CLpro, unveiling that its catalysis is critically dependent on the dynamics, which can be amazingly modulated by the extra domain. Consequently, mediating the dynamics may offer a potential avenue to inhibit the SARS-CoV 3CLpro.
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