6W7A
The crystal structure of the 2009/H1N1/California PA endonuclease mutant E119D bound to DNA oligomer TAGCAT (uncleaved, 5mM overnight DNA soak)
Summary for 6W7A
| Entry DOI | 10.2210/pdb6w7a/pdb |
| Related | 6W5P |
| Descriptor | Protein PA-X,Polymerase acidic protein, DNA (5'-D(P*TP*AP*GP*CP*AP*T)-3'), GLYCEROL, ... (6 entities in total) |
| Functional Keywords | nuclease, influenza, dna oligomer, uncleaved, viral protein, viral protein-dna complex, viral protein/dna |
| Biological source | Influenza A virus More |
| Total number of polymer chains | 2 |
| Total formula weight | 25886.12 |
| Authors | Cuypers, M.G.,Kumar, G.,Webb, T.,White, S.W. (deposition date: 2020-03-18, release date: 2021-02-03, Last modification date: 2023-10-25) |
| Primary citation | Kumar, G.,Cuypers, M.,Webby, R.R.,Webb, T.R.,White, S.W. Structural insights into the substrate specificity of the endonuclease activity of the influenza virus cap-snatching mechanism. Nucleic Acids Res., 49:1609-1618, 2021 Cited by PubMed 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. PubMed: 33469660DOI: 10.1093/nar/gkaa1294 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.09 Å) |
Structure validation
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