4YYL

Phenolic acid derivative bound to influenza strain H1N1 polymerase subunit PA endonuclease

Summary for 4YYL

• Entry DOI: 10.2210/pdb4yyl/pdb
• Descriptor: Polymerase acidic protein, 2-(4-fluorophenoxy)-1-(2,3,4-trihydroxyphenyl)ethanone, MANGANESE (II) ION, ... (5 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Influenza A virus (strain A/Puerto Rico/8/1934 H1N1); More
• Total number of polymer chains: 1
• Total formula weight: 23341.13

Authors

Fudo, S.,Yamamoto, N.,Nukaga, M.,Odagiri, T.,Tashiro, M.,Neya, S.,Hoshino, T. (deposition date: 2015-03-24, release date: 2015-04-29, Last modification date: 2023-11-08)

Primary citation

Fudo, S.,Yamamoto, N.,Nukaga, M.,Odagiri, T.,Tashiro, M.,Neya, S.,Hoshino, T.
Structural and computational study on inhibitory compounds for endonuclease activity of influenza virus polymerase
Bioorg.Med.Chem., 23:5466-5475, 2015

PubMed Abstract: Seasonal epidemics and occasional pandemics caused by influenza viruses are global threats to humans. Since the efficacy of currently approved drugs is limited by the emerging resistance of the viruses, the development of new antiviral drugs is still demanded. Endonuclease activity, which lies in the influenza polymerase acidic protein N-terminal domain (PA(N)), is a potent target for novel antiviral agents. Here, we report the identification of some novel inhibitors for PA(N) endonuclease activity. The binding mode of one of the inhibitory compounds to PA(N) was investigated in detail by means of X-ray crystal structure analysis and molecular dynamics (MD) simulation. It was observed in the crystal structure that three molecules of the same kind of inhibitor were bound to one PA(N). One of the three molecules is located at the active site and makes a chelation to metal ions. Another molecule is positioned at the space adjacent to the metal-chelated site. The other molecule is located at a site slightly apart from the metal-chelated site, causing a conformational change of Arg124. The last binding site was not observed in previous crystallographic studies. Hence, the stability of inhibitor binding was examined by performing 100-ns MD simulation. During the MD simulation, the three inhibitor molecules fluctuated at the respective binding sites at different amplitudes, while all of the molecules maintained interactions with the protein. Molecular mechanics/generalized Born surface area (MM/GBSA) analysis suggested that the molecule in the last binding site has a higher affinity than the others. Structural information obtained in this study will provide a hint for designing and developing novel potent agents against influenza viruses.

PubMed: 26252962
DOI: 10.1016/j.bmc.2015.07.046

Experimental method

X-RAY DIFFRACTION (1.905 Å)