ArticleJournal of virology2006
West Nile virus 5'-cap structure is formed by sequential guanine N-7 and ribose 2'-O methylations by nonstructural protein 5.
Article in Journal of virology, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 226 papers.
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Who cites it
226 citing papers in PubMed, 379 citations in OpenAlex.
- Article
- Lost in translation: interferon-stimulated genes targeting flavivirus protein synthesis.Journal of virology · 2026Review
- An orthoflavivirus inhibitor targeting multifunctional NS2A protein, a previously unidentified target.PLoS pathogens · 2026Article
- Pharmaceutical Strategies for West Nile Virus in Europe, an Underrecognized Cause of Severe Disease and Mortality in Older Adults: From Supportive Care to Antiviral Development.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Design, synthesis and evaluation of arylpurine-based sinefungin mimetics as zika virus methyltransferase inhibitors.RSC advances · 2025Article
- Influenza A virus RNA localisation and the interceding trafficking pathways of the host cell.PLoS pathogens · 2025Review
- Mechanistic insights into dengue virus inhibition by a clinical trial compound NITD-688.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Exposure of negative-sense viral RNA in the cytoplasm initiates innate immunity to West Nile virus.Molecular cell · 2025Article
- West Nile virus unmasked: from gene variability to future challenges.Frontiers in cellular and infection microbiology · 2025Review
- Role of the epitranscriptome in viral infections: beneficial or detrimental?Memorias do Instituto Oswaldo Cruz · 2025Review
- Identification of a putative new virus from theVirus evolution · 2025Article
- West Nile virus - a re-emerging global threat: recent advances in vaccines and drug discovery.Frontiers in cellular and infection microbiology · 2025Review
- 2'-O-methyltransferase-deficient yellow fever virus: Restricted replication in the midgut and secondary tissues of Aedes aegypti mosquitoes severely limits dissemination.PLoS pathogens · 2024Article
- Article
- Multi-omics analysis of antiviral interactions of Elizabethkingia anophelis and Zika virus.Scientific reports · 2024Article
- Structural and functional insights into the 2'-O-methyltransferase of SARS-CoV-2.Virologica Sinica · 2024Article
- Natural evidence of coronaviral 2'-O-methyltransferase activity affecting viral pathogenesis via improved substrate RNA binding.Signal transduction and targeted therapy · 2024Article
- Residue K28 of Zika Virus NS5 Protein Is Implicated in Virus Replication and Antagonism of STAT2.Microorganisms · 2024Article
- The Dynamic Landscape of Capsid Proteins and Viral RNA Interactions in Flavivirus Genome Packaging and Virus Assembly.Pathogens (Basel, Switzerland) · 2024Review
- Development in the Inhibition of Dengue Proteases as Drug Targets.Current medicinal chemistry · 2024Review
166 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Many flaviviruses are globally important human pathogens. Their plus-strand RNA genome contains a 5'-cap structure that is methylated at the guanine N-7 and the ribose 2'-OH positions of the first transcribed nucleotide, adenine (m(7)GpppAm). Using West Nile virus (WNV), we demonstrate, for the first time, that the nonstructural protein 5 (NS5) mediates both guanine N-7 and ribose 2'-O methylations and therefore is essential for flavivirus 5'-cap formation. We show that a recombinant full-length and a truncated NS5 protein containing the methyltransferase (MTase) domain methylates GpppA-capped and m(7)GpppA-capped RNAs to m(7)GpppAm-RNA, using S-adenosylmethionine as a methyl donor. Furthermore, methylation of GpppA-capped RNA sequentially yielded m(7)GpppA- and m(7)GpppAm-RNA products, indicating that guanine N-7 precedes ribose 2'-O methylation. Mutagenesis of a K(61)-D(146)-K(182)-E(218) tetrad conserved in other cellular and viral MTases suggests that NS5 requires distinct amino acids for its N-7 and 2'-O MTase activities. The entire K(61)-D(146)-K(182)-E(218) motif is essential for 2'-O MTase activity, whereas N-7 MTase activity requires only D(146). The other three amino acids facilitate, but are not essential for, guanine N-7 methylation. Amino acid substitutions within the K(61)-D(146)-K(182)-E(218) motif in a WNV luciferase-reporting replicon significantly reduced or abolished viral replication in cells. Additionally, the mutant MTase-mediated replication defect could not be trans complemented by a wild-type replicase complex. These findings demonstrate a critical role for the flavivirus MTase in viral reproduction and underscore this domain as a potential target for antiviral therapy.
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