ArticleThe Journal of biological chemistry2016
Hydrogen/Deuterium Exchange Kinetics Demonstrate Long Range Allosteric Effects of Thumb Site 2 Inhibitors of Hepatitis C Viral RNA-dependent RNA Polymerase.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
What it found
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Who cites it
16 citing papers in PubMed, 28 citations in OpenAlex.
- Protein structural dynamics in covalent drug design: insights from irreversible and reversible covalent inhibitors.RSC chemical biology · 2026Review
- Structural dynamics of the dengue virus non-structural 5 (NS5) interactions with promoter stem-loop A (SLA).Npj viruses · 2025Article
- Fluorescence, Circular Dichroism and Mass Spectrometry as Tools to Study Virus Structure.Sub-cellular biochemistry · 2024Review
- 14-3-3 protein inhibits CaMKK1 by blocking the kinase active site with its last two C-terminal helices.Protein science : a publication of the Protein Society · 2023Article
- The IQA Energy Partition in a Drug Design Setting: A Hepatitis C Virus RNA-Dependent RNA Polymerase (NS5B) Case Study.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Hydrogen/Deuterium Exchange and Nuclear Magnetic Resonance Spectroscopy Reveal Dynamic Allostery on Multiple Time Scales in the Serine Protease Thrombin.Biochemistry · 2021Article
- Hepatitis C Viral Replication Complex.Viruses · 2021Review
- Mass Spectrometry-Based Structural Virology.Analytical chemistry · 2021Review
- Fatty Acid Allosteric Regulation of C-H Activation in Plant and Animal Lipoxygenases.Molecules (Basel, Switzerland) · 2020Review
- Fast photochemical oxidation of proteins (FPOP): A powerful mass spectrometry-based structural proteomics tool.The Journal of biological chemistry · 2019Review
- Hydrogen-deuterium exchange reveals long-range dynamical allostery in soybean lipoxygenase.The Journal of biological chemistry · 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
- Hydrogen-Deuterium Exchange of Lipoxygenase Uncovers a Relationship between Distal, Solvent Exposed Protein Motions and the Thermal Activation Barrier for Catalytic Proton-Coupled Electron Tunneling.ACS central science · 2017Article
- Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase.Viruses · 2017Article
- Ligand-induced allostery in the interaction of theProceedings of the National Academy of Sciences of the United States of America · 2017Article
- Thumb Site 2 Inhibitors of Hepatitis C Viral RNA-dependent RNA Polymerase Allosterically Block the Transition from Initiation to Elongation.The Journal of biological chemistry · 2016Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
New nonnucleoside analogs are being developed as part of a multi-drug regimen to treat hepatitis C viral infections. Particularly promising are inhibitors that bind to the surface of the thumb domain of the viral RNA-dependent RNA polymerase (NS5B). Numerous crystal structures have been solved showing small molecule non-nucleoside inhibitors bound to the hepatitis C viral polymerase, but these structures alone do not define the mechanism of inhibition. Our prior kinetic analysis showed that nonnucleoside inhibitors binding to thumb site-2 (NNI2) do not block initiation or elongation of RNA synthesis; rather, they block the transition from the initiation to elongation, which is thought to proceed with significant structural rearrangement of the enzyme-RNA complex. Here we have mapped the effect of three NNI2 inhibitors on the conformational dynamics of the enzyme using hydrogen/deuterium exchange kinetics. All three inhibitors rigidify an extensive allosteric network extending >40 Å from the binding site, thus providing a structural rationale for the observed disruption of the transition from distributive initiation to processive elongation. The two more potent inhibitors also suppress slow cooperative unfolding in the fingers extension-thumb interface and primer grip, which may contribute their stronger inhibition. These results establish that NNI2 inhibitors act through long range allosteric effects, reveal important conformational changes underlying normal polymerase function, and point the way to the design of more effective allosteric inhibitors that exploit this new information.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.