ArticlePLoS pathogens2012
Molecular basis for nucleotide conservation at the ends of the dengue virus genome.
Article in PLoS pathogens, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 78 citations in OpenAlex.
- Computational approaches for flavivirus drug discovery: targeting structural and non-structural proteins.RSC medicinal chemistry · 2026Review
- Positive-Strand RNA Viral RdRps: From Structure Conservation and Activity Assay to Drug Development.Molecules (Basel, Switzerland) · 2026Review
- The RNA promoter for pathogenic orthoflaviviruses replication is universal and serves as target for viral inhibition.PLoS pathogens · 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
- Structural insights into polymerase-catalyzed FAD capping of hepatitis C virus RNA.Nature communications · 2025Article
- Functional Roles and Host Interactions ofPathogens (Basel, Switzerland) · 2025Review
- The Flavivirus Non-Structural Protein 5 (NS5): Structure, Functions, and Targeting for Development of Vaccines and Therapeutics.Vaccines · 2024Review
- The myriad roles of RNA structure in the flavivirus life cycle.RNA biology · 2024Review
- Galidesivir Triphosphate Promotes Stalling of Dengue-2 Virus Polymerase Immediately Prior to Incorporation.ACS infectious diseases · 2023Article
- A conserved arginine in NS5 binds genomic 3' stem-loop RNA for primer-independent initiation of flavivirus RNA replication.RNA (New York, N.Y.) · 2022Article
- Identification of 6ω-cyclohexyl-2-(phenylamino carbonylmethylthio)pyrimidin-4(3Frontiers in chemistry · 2022Article
- Snapshots of a Non-Canonical RdRP in Action.Viruses · 2021Article
- Review
- Structures of flavivirus RNA promoters suggest two binding modes with NS5 polymerase.Nature communications · 2021Article
- The Pseudo-Circular Genomes of Flaviviruses: Structures, Mechanisms, and Functions of Circularization.Cells · 2021Review
- Two RNA Tunnel Inhibitors Bind in Highly Conserved Sites in Dengue Virus NS5 Polymerase: Structural and Functional Studies.Journal of virology · 2020Article
- Mechanistic cross-talk between DNA/RNA polymerase enzyme kinetics and nucleotide substrate availability in cells: Implications for polymerase inhibitor discovery.The Journal of biological chemistry · 2020Review
- Article
- The C-Terminal Domain of the Sudan Ebolavirus L Protein Is Essential for RNA Binding and Methylation.Journal of virology · 2020Article
- Polymerase Activity, Protein-Protein Interaction, and Cellular Localization of the Usutu Virus NS5 Protein.Antimicrobial agents and chemotherapy · 2019Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The dengue virus (DV) is an important human pathogen from the Flavivirus genus, whose genome- and antigenome RNAs start with the strictly conserved sequence pppAG. The RNA-dependent RNA polymerase (RdRp), a product of the NS5 gene, initiates RNA synthesis de novo, i.e., without the use of a pre-existing primer. Very little is known about the mechanism of this de novo initiation and how conservation of the starting adenosine is achieved. The polymerase domain NS5Pol(DV) of NS5, upon initiation on viral RNA templates, synthesizes mainly dinucleotide primers that are then elongated in a processive manner. We show here that NS5Pol(DV) contains a specific priming site for adenosine 5'-triphosphate as the first transcribed nucleotide. Remarkably, in the absence of any RNA template the enzyme is able to selectively synthesize the dinucleotide pppAG when Mn(2+) is present as catalytic ion. The T794 to A799 priming loop is essential for initiation and provides at least part of the ATP-specific priming site. The H798 loop residue is of central importance for the ATP-specific initiation step. In addition to ATP selection, NS5Pol(DV) ensures the conservation of the 5'-adenosine by strongly discriminating against viral templates containing an erroneous 3'-end nucleotide in the presence of Mg(2+). In the presence of Mn(2+), NS5Pol(DV) is remarkably able to generate and elongate the correct pppAG primer on these erroneous templates. This can be regarded as a genomic/antigenomic RNA end repair mechanism. These conservational mechanisms, mediated by the polymerase alone, may extend to other RNA virus families having RdRps initiating RNA synthesis de novo.
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