ArticleProtein science : a publication of the Protein Society2014
The crystal structure of NS5A domain 1 from genotype 1a reveals new clues to the mechanism of action for dimeric HCV inhibitors.
Article in Protein science : a publication of the Protein Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 99 citations in OpenAlex.
- A novel dimerization site in non-structural protein 5A of hepatitis C virus regulates viral replication fitness.PLoS pathogens · 2026Article
- Phospholipid-driven conformational switching of HCV NS5A links protein folding to replication membrane remodeling.Science advances · 2026Article
- A key role for hepatitis C virus NS5A serine 225 phosphorylation revealed by super-resolution microscopy.Scientific reports · 2025Article
- Sub-stoichiometric Modulation of Viral Targets-Potent Antiviral Agents That Exploit Target Vulnerability.ACS medicinal chemistry letters · 2023Article
- Going Viral: An Investigation into the Chameleonic Behaviour of Antiviral Compounds.Chemistry (Weinheim an der Bergstrasse, Germany) · 2023Article
- NS5A domain I antagonises PKR to facilitate the assembly of infectious hepatitis C virus particles.PLoS pathogens · 2023Article
- Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells.Scientific reports · 2022Article
- Article
- Regulatory Role of Phospholipids in Hepatitis C Virus Replication and Protein Function.Pathogens (Basel, Switzerland) · 2022Review
- The Discovery of Conformationally Constrained Bicyclic Peptidomimetics as Potent Hepatitis C NS5A Inhibitors.ACS medicinal chemistry letters · 2021Article
- NS5A-ISGylation via Lysine 26 Has a Critical Role for Efficient Propagation of Hepatitis C Virus Genotype 2a.The Kobe journal of medical sciences · 2021Article
- Hepatitis C Viral Replication Complex.Viruses · 2021Review
- Dimer Organization of Membrane-Associated NS5A of Hepatitis C Virus as Determined by Highly SensitiveAngewandte Chemie (International ed. in English) · 2021Article
- Molecular Events Occurring in Lipophagy and Its Regulation inFrontiers in microbiology · 2021Review
- Amino Acid Substitutions Associated with Treatment Failure for Hepatitis C Virus Infection.Journal of clinical microbiology · 2020Article
- ISGylation of Hepatitis C Virus NS5A Protein Promotes Viral RNA Replication via Recruitment of Cyclophilin A.Journal of virology · 2020Article
- Ribosome Pausing at Inefficient Codons at the End of the Replicase Coding Region Is Important for Hepatitis C Virus Genome Replication.International journal of molecular sciences · 2020Article
- Phenotypic analysis of mutations at residue 146 provides insights into the relationship between NS5A hyperphosphorylation and hepatitis C virus genome replication.The Journal of general virology · 2020Article
- Interplay of Amino Acid Residues at Positions 28 and 31 in NS5A Defines Resistance Pathways in HCV GT2.Antimicrobial agents and chemotherapy · 2019Article
- Cyclophilin A allows the allosteric regulation of a structural motif in the disordered domain 2 of NS5A and thereby fine-tunes HCV RNA replication.The Journal of biological chemistry · 2019Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
New direct acting antivirals (DAAs) such as daclatasvir (DCV; BMS-790052), which target NS5A function with picomolar potency, are showing promise in clinical trials. The exact nature of how these compounds have an inhibitory effect on HCV is unknown; however, major resistance mutations appear in the N-terminal region of NS5A that include the amphipathic helix and domain 1. The dimeric symmetry of these compounds suggests that they act on a dimer of NS5A, which is also consistent with the presence of dimers in crystals of NS5A domain 1 from genotype 1b. Genotype 1a HCV is less potently affected by these compounds and resistance mutations have a greater effect than in the 1b genotypes. We have obtained crystals of domain 1 of the important 1a NS5A homologue and intriguingly, our X-ray crystal structure reveals two new dimeric forms of this domain. Furthermore, the high solvent content (75%) makes it ideal for ligand-soaking. Daclatasvir (DCV) shows twofold symmetry suggesting NS5A dimers may be of physiological importance and serve as potential binding sites for DCV. These dimers also allow for new conformations of a NS5A expansive network which could explain its operation on the membranous web. Additionally, sulfates bound in the crystal structure may provide evidence for the previously proposed RNA binding groove, or explain regulation of NS5A domain 2 and 3 function and phosphorylation, by domain 1.
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