ArticlePloS one2014
Structural and regulatory elements of HCV NS5B polymerase--β-loop and C-terminal tail--are required for activity of allosteric thumb site II inhibitors.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Integrated deep learning and multi-scale modeling for the discovery of pan-genotypic HCV NS5B polymerase inhibitors.Molecular diversity · 2026Article
- Discovery of non-nucleoside inhibitors of the enterovirus D68 3D polymerase through crystallographic fragment and high-throughput biochemical screening.bioRxiv : the preprint server for biology · 2026Article
- Rapid phylogenomic analysis for viral surveillance and metagenomic profiling with Omni2Tree.bioRxiv : the preprint server for biology · 2026Article
- Crystallographic Fragment Screening of the Dengue Virus Polymerase Reveals Multiple Binding Sites for the Development of Non-nucleoside Antiflavivirals.Journal of medicinal chemistry · 2025Article
- Review
- Geometric Deep learning Prioritization and Validation of Cannabis Phytochemicals as Anti-HCV Non-nucleoside Direct-acting Inhibitors.Biomedical engineering and computational biology · 2024Article
- The IQA Energy Partition in a Drug Design Setting: A Hepatitis C Virus RNA-Dependent RNA Polymerase (NS5B) Case Study.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Design and synthesis of pyrazolone-based compounds as potent blockers of SARS-CoV-2 viral entry into the host cells.Journal of molecular structure · 2021Article
- Design, Synthesis, Molecular Modeling Studies and Biological Evaluation of N'-Arylidene-6-(benzyloxy)-4-oxo-1,4-dihydroquinoline-3-carbohydrazide Derivatives as Novel Anti-HCV Agents.Iranian journal of pharmaceutical research : IJPR · 2019Article
- Targeting HCV polymerase: a structural and dynamic perspective into the mechanism of selective covalent inhibition.RSC advances · 2018Article
- Baseline dasabuvir resistance in Hepatitis C virus from the genotypes 1, 2 and 3 and modeling of the NS5B-dasabuvir complex by theInfection ecology & epidemiology · 2018Article
- NMR reveals the intrinsically disordered domain 2 of NS5A protein as an allosteric regulator of the hepatitis C virus RNA polymerase NS5B.The Journal of biological chemistry · 2017Article
- Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase.Viruses · 2017Article
- Hydrogen/Deuterium Exchange Kinetics Demonstrate Long Range Allosteric Effects of Thumb Site 2 Inhibitors of Hepatitis C Viral RNA-dependent RNA Polymerase.The Journal of biological chemistry · 2016Article
- Allosteric inhibitors of Coxsackie virus A24 RNA polymerase.Bioorganic & medicinal chemistry · 2016Article
- Biochemical Effect of Resistance Mutations against Synergistic Inhibitors of RSV RNA Polymerase.PloS one · 2016Article
- The juxtamembrane sequence of the Hepatitis C virus polymerase can affect RNA synthesis and inhibition by allosteric polymerase inhibitors.Virus genes · 2015Article
- Combination of pharmacophore hypothesis and molecular docking to identify novel inhibitors of HCV NS5B polymerase.Molecular diversity · 2015Article
- Review
- Hydrophobic and charged residues in the C-terminal arm of hepatitis C virus RNA-dependent RNA polymerase regulate initiation and elongation.Journal of virology · 2015Article
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Authors and funding
14 authors.
Funding
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Abstract
Elucidation of the mechanism of action of the HCV NS5B polymerase thumb site II inhibitors has presented a challenge. Current opinion holds that these allosteric inhibitors stabilize the closed, inactive enzyme conformation, but how this inhibition is accomplished mechanistically is not well understood. Here, using a panel of NS5B proteins with mutations in key regulatory motifs of NS5B--the C-terminal tail and β-loop--in conjunction with a diverse set of NS5B allosteric inhibitors, we show that thumb site II inhibitors possess a distinct mechanism of action. A combination of enzyme activity studies and direct binding assays reveals that these inhibitors require both regulatory elements to maintain the polymerase inhibitory activity. Removal of either element has little impact on the binding affinity of thumb site II inhibitors, but significantly reduces their potency. NS5B in complex with a thumb site II inhibitor displays a characteristic melting profile that suggests stabilization not only of the thumb domain but also the whole polymerase. Successive truncations of the C-terminal tail and/or removal of the β-loop lead to progressive destabilization of the protein. Furthermore, the thermal unfolding transitions characteristic for thumb site II inhibitor-NS5B complex are absent in the inhibitor-bound constructs in which interactions between C-terminal tail and β-loop are abolished, pointing to the pivotal role of both regulatory elements in communication between domains. Taken together, a comprehensive picture of inhibition by compounds binding to thumb site II emerges: inhibitor binding provides stabilization of the entire polymerase in an inactive, closed conformation, propagated via coupled interactions between the C-terminal tail and β-loop.
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