ArticleProceedings of the National Academy of Sciences of the United States of America2010
Three conformational snapshots of the hepatitis C virus NS3 helicase reveal a ratchet translocation mechanism.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 144 papers.
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Who cites it
144 citing papers in PubMed.
- Cryo-EM structures of human FANCJ reveal the mechanism of G-quadruplex unwinding and disease-associated mutations.Nature communications · 2026Article
- Allosteric Regulation of RNA Affinity by Motif V-VI Coupling in West Nile Virus NS3 Helicase.Proteins · 2026Article
- Asymmetric dimeric assembly of Suv3 helicase facilitates processive RNA unwinding.Nature communications · 2026Article
- Motif V is an allosteric couple between the SARS-CoV-2 nsp13 nucleotide triphosphatase and helicase active sites.The Journal of biological chemistry · 2026Article
- Review
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- Hepatitis C virus NS3 helicase contributes to (-) strand RNA synthesis.Nature communications · 2025Article
- Pathogenesis, prevention, and therapeutic advances in hepatitis B, C, and D.Virology journal · 2025Review
- Biochemical and structural basis of Dicer helicase function unveiled by resurrecting ancient proteins.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Review
- Structural Chemistry of Helicase Inhibition.Journal of medicinal chemistry · 2025Review
- Analogs of NIH Molecular Probe ML283 Are Potent SARS-CoV-2 Helicase Inhibitors.ACS chemical biology · 2025Article
- A gate-clamp mechanism for ssDNA translocation by DdmD in Vibrio cholerae plasmid defense.Nucleic acids research · 2025Article
- The Role of SF1 and SF2 Helicases in Biotechnological Applications.Applied biochemistry and biotechnology · 2024Review
- Helicase-assisted continuous editing for programmable mutagenesis of endogenous genomes.Science (New York, N.Y.) · 2024Article
- Article
- Suppression of inositol pyrophosphate toxicosis and hyper-repression of the fission yeastmBio · 2024Article
- Energy-driven genome regulation by ATP-dependent chromatin remodellers.Nature reviews. Molecular cell biology · 2024Review
- Using a Function-First "Scout Fragment"-Based Approach to Develop Allosteric Covalent Inhibitors of Conformationally Dynamic Helicase Mechanoenzymes.Journal of the American Chemical Society · 2024Article
- Conformational Changes and ATP Hydrolysis in Zika Helicase: The Molecular Basis of a Biomolecular Motor Unveiled by Multiscale Simulations.Journal of the American Chemical Society · 2023Article
84 more citing papers are in PubMed but not listed here.
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2 authors.
Funding
Abstract
A virally encoded superfamily-2 (SF2) helicase (NS3h) is essential for the replication of hepatitis C virus, a leading cause of liver disease worldwide. Efforts to elucidate the function of NS3h and to develop inhibitors against it, however, have been hampered by limited understanding of its molecular mechanism. Here we show x-ray crystal structures for a set of NS3h complexes, including ground-state and transition-state ternary complexes captured with ATP mimics (ADP.BeF(3) and ). These structures provide, for the first time, three conformational snapshots demonstrating the molecular basis of action for a SF2 helicase. Upon nucleotide binding, overall domain rotation along with structural transitions in motif V and the bound DNA leads to the release of one base from the substrate base-stacking row and the loss of several interactions between NS3h and the 3' DNA segment. As nucleotide hydrolysis proceeds into the transition state, stretching of a "spring" helix and another overall conformational change couples rearrangement of the (d)NTPase active site to additional hydrogen-bonding between NS3h and DNA. Together with biochemistry, these results demonstrate a "ratchet" mechanism involved in the unidirectional translocation and define the step size of NS3h as one base per nucleotide hydrolysis cycle. These findings suggest feasible strategies for developing specific inhibitors to block the action of this attractive, yet largely unexplored drug target.
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