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PDBsum entry 4zqq
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References listed in PDB file
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Key reference
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Title
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Two distinctive binding modes of endonuclease inhibitors to the n-Terminal region of influenza virus polymerase acidic subunit.
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Authors
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S.Fudo,
N.Yamamoto,
M.Nukaga,
T.Odagiri,
M.Tashiro,
T.Hoshino.
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Ref.
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Biochemistry, 2016,
55,
2646-2660.
[DOI no: ]
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PubMed id
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Abstract
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Influenza viruses are global threat to humans, and the development of new
antiviral agents are still demanded to prepare for pandemics and to overcome the
emerging resistance to the current drugs. Influenza polymerase acidic protein
N-terminal domain (PAN) has endonuclease activity and is one of the appropriate
targets for novel antiviral agents. First, we performed X-ray cocrystal analysis
on the complex structures of PAN with two endonuclease inhibitors. The protein
crystallization and the inhibitor soaking were done at pH 5.8. The binding modes
of the two inhibitors were different from a common binding mode previously
reported for the other influenza virus endonuclease inhibitors. We additionally
clarified the complex structures of PAN with the same two endonuclease
inhibitors at pH 7.0. In one of the crystal structures, an additional inhibitor
molecule, which chelated to the two metal ions in the active site, was observed.
On the basis of the crystal structures at pH 7.0, we carried out 100 ns
molecular dynamics (MD) simulations for both of the complexes. The analysis of
simulation results suggested that the binding mode of each inhibitor to PAN was
stable in spite of the partial deviation of the simulation structure from the
crystal one. Furthermore, crystal structure analysis and MD simulation were
performed for PAN in complex with an inhibitor, which was already reported to
have a high compound potency for comparison. The findings on the presence of
multiple binding sites at around the PAN substrate-binding pocket will provide a
hint for enhancing the binding affinity of inhibitors.
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