ArticleJournal of virology2012
Two crucial early steps in RNA synthesis by the hepatitis C virus polymerase involve a dual role of residue 405.
Article in Journal of virology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Structural insights into polymerase-catalyzed FAD capping of hepatitis C virus RNA.Nature communications · 2025Article
- Viral Capsid and Polymerase in Reoviridae.Sub-cellular biochemistry · 2022Article
- Article
- Hepatitis C Viral Replication Complex.Viruses · 2021Review
- 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
- Review
- Cross-genotypic examination of hepatitis C virus polymerase inhibitors reveals a novel mechanism of action for thumb binders.Antimicrobial agents and chemotherapy · 2014Article
- Inhibition of viral RNA polymerases by nucleoside and nucleotide analogs: therapeutic applications against positive-strand RNA viruses beyond hepatitis C virus.Current opinion in virology · 2014Review
- Hepatitis C virus RNA replication and assembly: living on the fat of the land.Cell host & microbe · 2014Review
- Molecular and structural basis for the roles of hepatitis C virus polymerase NS5B amino acids 15, 223, and 321 in viral replication and drug resistance.Antimicrobial agents and chemotherapy · 2014Article
- The methyltransferase domain of dengue virus protein NS5 ensures efficient RNA synthesis initiation and elongation by the polymerase domain.Nucleic acids research · 2014Article
- The hepatitis C virus core protein can modulate RNA-dependent RNA synthesis by the 2a polymerase.Virus research · 2014Article
- Efficiency of incorporation and chain termination determines the inhibition potency of 2'-modified nucleotide analogs against hepatitis C virus polymerase.Antimicrobial agents and chemotherapy · 2014Article
- Construction of a chimeric hepatitis C virus replicon based on a strain isolated from a chronic hepatitis C patient.Virologica Sinica · 2014Article
- Article
- Hepatitis C virus RNA replication.Current topics in microbiology and immunology · 2013Review
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The hepatitis C virus (HCV) NS5B protein is an RNA-dependent RNA polymerase essential for replication of the viral RNA genome. In vitro and presumably in vivo, NS5B initiates RNA synthesis by a de novo mechanism and then processively copies the whole RNA template. Dissections of de novo RNA synthesis by genotype 1 NS5B proteins previously established that there are two successive crucial steps in de novo initiation. The first is dinucleotide formation, which requires a closed conformation, and the second is the transition to elongation, which requires an opening of NS5B. We also recently published a combined structural and functional analysis of genotype 2 HCV-NS5B proteins (of strains JFH1 and J6) that established residue 405 as a key element in de novo RNA synthesis (P. Simister et al., J. Virol. 83:11926-11939, 2009; M. Schmitt et al., J. Virol 85:2565-2581, 2011). We hypothesized that this residue stabilizes a particularly closed conformation conducive to dinucleotide formation. Here we report similar in vitro dissections of de novo synthesis for J6 and JFH1 NS5B proteins, as well as for mutants at position 405 of several genotype 1 and 2 strains. Our results show that an isoleucine at position 405 can promote both dinucleotide formation and the transition to elongation. New structural results highlight a molecular switch of position 405 with long-range effects, resolving the implied paradox of how the same residue can successively favor both the closed conformation of the dinucleotide formation step and the opening necessary to the transition step.
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