5EGA

2009 H1N1 PA endonuclease domain in complex with an N-acylhydrazone inhibitor

Summary for 5EGA

• Entry DOI: 10.2210/pdb5ega/pdb
• Related: 5DES
• Descriptor: Polymerase acidic protein, MANGANESE (II) ION, 3,4,5-tris(oxidanyl)-~{N}-[(~{E})-[3,4,5-tris(oxidanyl)phenyl]methylideneamino]benzamide, ... (4 entities in total)
• Functional Keywords: influenza, endonuclease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Influenza A virus; More
• Total number of polymer chains: 1
• Total formula weight: 22400.29

Authors

Kumar, G.,White, S.W. (deposition date: 2015-10-26, release date: 2016-08-31, Last modification date: 2023-09-27)

Primary citation

Carcelli, M.,Rogolino, D.,Gatti, A.,De Luca, L.,Sechi, M.,Kumar, G.,White, S.W.,Stevaert, A.,Naesens, L.
N-acylhydrazone inhibitors of influenza virus PA endonuclease with versatile metal binding modes.
Sci Rep, 6:31500-31500, 2016

PubMed Abstract: Influenza virus PA endonuclease has recently emerged as an attractive target for the development of novel antiviral therapeutics. This is an enzyme with divalent metal ion(s) (Mg(2+) or Mn(2+)) in its catalytic site: chelation of these metal cofactors is an attractive strategy to inhibit enzymatic activity. Here we report the activity of a series of N-acylhydrazones in an enzymatic assay with PA-Nter endonuclease, as well as in cell-based influenza vRNP reconstitution and virus yield assays. Several N-acylhydrazones were found to have promising anti-influenza activity in the low micromolar concentration range and good selectivity. Computational docking studies are carried on to investigate the key features that determine inhibition of the endonuclease enzyme by N-acylhydrazones. Moreover, we here describe the crystal structure of PA-Nter in complex with one of the most active inhibitors, revealing its interactions within the protein's active site.

PubMed: 27510745
DOI: 10.1038/srep31500

Experimental method

X-RAY DIFFRACTION (2.15 Å)