Summary information and primary citation
- PDB-id
-
7kl3;
DSSR-derived features in text and
JSON formats; DNAproDB
- Class
- viral protein-RNA
- Method
- X-ray (1.99 Å)
- Summary
- The crystal structure of the 2009-h1n1-california pa
endonuclease mutant e119d bound to RNA oligomer ag*cauc
(*uncleaveable bond, -uc disordered)
- Reference
-
Kumar G, Cuypers M, Webby RR, Webb TR, White SW (2021):
"Structural
insights into the substrate specificity of the
endonuclease activity of the influenza virus
cap-snatching mechanism." Nucleic Acids
Res., 49, 1609-1618. doi: 10.1093/nar/gkaa1294.
- 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.
