Journal
NUCLEIC ACIDS RESEARCH
Volume 49, Issue 3, Pages 1609-1618Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkaa1294
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Funding
- NIH [AI098757]
- Comprehensive Cancer Center [CA021765]
- American Lebanese Syrian Associated Charities (ALSAC)
- U.S. Department of Energy [W31-109-Eng-38]
- St. Jude Children's Research Hospital, Department of Structural Biology
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The endonuclease activity within the influenza virus cap-snatching process is a proven therapeutic target. Baloxavir, an anti-influenza drug, is effective but linked to resistance mutations. By studying complexes of PA(N) with RNA and DNA oligonucleotides, insights are gained on specificity and structural basis of baloxavir resistance mutations.
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 (PA(N)) of the influenza RNA dependent RNA polymerase, and we report here complexes of PA(N) 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 PA(N) 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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