7NUG

Influenza A/California/07/2009(H1N1) endonuclease in complex with orientin

Summary for 7NUG

• Entry DOI: 10.2210/pdb7nug/pdb
• Descriptor: Polymerase acidic protein,Polymerase acidic protein, MANGANESE (II) ION, MAGNESIUM ION, ... (9 entities in total)
• Functional Keywords: endonuclease, protein-ligand complex, rna polymerase, flavonoids, viral protein
• Biological source: Influenza A virus (A/California/07/2009(H1N1)); More
• Total number of polymer chains: 1
• Total formula weight: 22741.84

Authors

Radilova, K.,Brynda, J. (deposition date: 2021-03-12, release date: 2021-07-28, Last modification date: 2024-01-31)

Primary citation

Reiberger, R.,Radilova, K.,Kral, M.,Zima, V.,Majer, P.,Brynda, J.,Dracinsky, M.,Konvalinka, J.,Kozisek, M.,Machara, A.
Synthesis and In Vitro Evaluation of C-7 and C-8 Luteolin Derivatives as Influenza Endonuclease Inhibitors.
Int J Mol Sci, 22:-, 2021

PubMed Abstract: The part of the influenza polymerase PA subunit featuring endonuclease activity is a target for anti-influenza therapies, including the FDA-approved drug Xofluza. A general feature of endonuclease inhibitors is their ability to chelate Mg or Mn ions located in the enzyme's catalytic site. Previously, we screened a panel of flavonoids for PA inhibition and found luteolin and its C-glucoside orientin to be potent inhibitors. Through structural analysis, we identified the presence of a 3',4'-dihydroxyphenyl moiety as a crucial feature for sub-micromolar inhibitory activity. Here, we report results from a subsequent investigation exploring structural changes at the C-7 and C-8 positions of luteolin. Experimental IC values were determined by AlphaScreen technology. The most potent inhibitors were C-8 derivatives with inhibitory potencies comparable to that of luteolin. Bio-isosteric replacement of the C-7 hydroxyl moiety of luteolin led to a series of compounds with one-order-of-magnitude-lower inhibitory potencies. Using X-ray crystallography, we solved structures of the wild-type PA-N-terminal domain and its I38T mutant in complex with orientin at 1.9 Å and 2.2 Å resolution, respectively.

PubMed: 34299354
DOI: 10.3390/ijms22147735

Experimental method

X-RAY DIFFRACTION (1.9 Å)