ArticleNucleic acids research2021
Structural insights into the substrate specificity of the endonuclease activity of the influenza virus cap-snatching mechanism.
Article in Nucleic acids research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Clinical impact of baloxavir-induced PA I38T/M substitutions in diverse influenza populations: a systematic review and meta-analysis.Virus research · 2026Article
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- Inhibitors of the Machupo Virus L Endonuclease for Bolivian Hemorrhagic Fever Treatments.Microorganisms · 2026Article
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- Substituent size versus metal binding of inhibitors with variants of influenza endonuclease.Journal of inorganic biochemistry · 2026Article
- Dual Inhibition of PB2 and JAK2 for Influenza: A Strategy Combining Antiviral and Host-Directed Immune Modulation.Molecules (Basel, Switzerland) · 2026Article
- Anti-influenza drugs targeting trimeric RNA polymerase complex: From development to clinics.Acta pharmaceutica Sinica. B · 2026Review
- A scoping review of influenza RdRp-targeting inhibitors: mechanisms, clinical translation, and emerging challenges.Frontiers in microbiology · 2026Review
- Antiviral susceptibility monitoring: testing algorithm, methods, and findings for influenza season, 2023-2024.Antiviral research · 2025Article
- Article
- Mutagenesis studies suggest a mechanism for influenza polymerase stalling during polyadenylation.Nucleic acids research · 2025Article
- Structural Studies of Inhibitors with Clinically Relevant Influenza Endonuclease Variants.Biochemistry · 2024Article
- Structural insights into viral genome replication by the severe fever with thrombocytopenia syndrome virus L protein.Nucleic acids research · 2023Article
- Influenza A virus polymerase acidic protein E23G/K substitutions weaken key baloxavir drug-binding contacts with minimal impact on replication and transmission.PLoS pathogens · 2022Article
- Alpha-hydroxytropolones are noncompetitive inhibitors of human RNase H1 that bind to the active site and modulate substrate binding.The Journal of biological chemistry · 2022Article
- Insights into Two-Metal-Ion Catalytic Mechanism of Cap-Snatching Endonuclease of Ebinur Lake Virus inJournal of virology · 2022Article
- Structure of Rift Valley Fever Virus RNA-Dependent RNA Polymerase.Journal of virology · 2022Article
- Not making the cut: Techniques to prevent RNA cleavage in structural studies of RNase-RNA complexes.Journal of structural biology: X · 2022Review
- Exploration of the 2,3-dihydroisoindole pharmacophore for inhibition of the influenza virus PA endonuclease.Bioorganic chemistry · 2021Article
- The active form of the influenza cap-snatching endonuclease inhibitor baloxavir marboxil is a tight binding inhibitor.The Journal of biological chemistryArticle
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5 authors.
Funding
Abstract
The endonuclease activity within the influenza virus cap-snatching process is a proven therapeutic target. The anti-influenza drug baloxavir is highly effective, but is associated with resistance mutations that threaten its clinical efficacy. The endonuclease resides within the N-terminal domain of the PA subunit (PAN) of the influenza RNA dependent RNA polymerase, and we report here complexes of PAN with RNA and DNA oligonucleotides to understand its specificity and the structural basis of baloxavir resistance mutations. The RNA and DNA oligonucleotides bind within the substrate binding groove of PAN in a similar fashion, explaining the ability of the enzyme to cleave both substrates. The individual nucleotides occupy adjacent conserved pockets that flank the two-metal active site. However, the 2' OH of the RNA ribose moieties engage in additional interactions that appear to optimize the binding and cleavage efficiency for the natural substrate. The major baloxavir resistance mutation at position 38 is at the core of the substrate binding site, but structural studies and modeling suggest that it maintains the necessary virus fitness via compensating interactions with RNA. These studies will facilitate the development of new influenza therapeutics that spatially match the substrate and are less likely to elicit resistance mutations.
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