6E3M
The N-terminal domain of PA endonuclease from the influenza H1N1 virus in complex with 6-(3-carboxyphenyl)-3-hydroxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid
Summary for 6E3M
| Entry DOI | 10.2210/pdb6e3m/pdb |
| Descriptor | Polymerase acidic protein, MANGANESE (II) ION, 1,2-ETHANEDIOL, ... (5 entities in total) |
| Functional Keywords | pa endonuclease, inhibitor, influenza, h1n1, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Influenza A virus |
| Total number of polymer chains | 1 |
| Total formula weight | 22915.82 |
| Authors | Morrison, C.N.,Dick, B.L.,Credille, C.V.,Cohen, S.M. (deposition date: 2018-07-14, release date: 2019-07-17, Last modification date: 2024-03-13) |
| Primary citation | Credille, C.V.,Morrison, C.N.,Stokes, R.W.,Dick, B.L.,Feng, Y.,Sun, J.,Chen, Y.,Cohen, S.M. SAR Exploration of Tight-Binding Inhibitors of Influenza Virus PA Endonuclease. J.Med.Chem., 62:9438-9449, 2019 Cited by PubMed Abstract: Significant efforts have been reported on the development of influenza antivirals including inhibitors of the RNA-dependent RNA polymerase PA N-terminal (PA) endonuclease. Based on recently identified, highly active metal-binding pharmacophores (MBPs) for PA endonuclease inhibition, a fragment-based drug development campaign was pursued. Guided by coordination chemistry and structure-based drug design, MBP scaffolds were elaborated to improve activity and selectivity. Structure-activity relationships were established and used to generate inhibitors of influenza endonuclease with tight-binding affinities. The activity of these inhibitors was analyzed using a fluorescence-quenching-based nuclease activity assay, and binding was validated using differential scanning fluorometry. Lead compounds were found to be highly selective for PA endonuclease against several related dinuclear and mononuclear metalloenzymes. Combining principles of bioinorganic and medicinal chemistry in this study has resulted in some of the most active in vitro influenza PA endonuclease inhibitors with high ligand efficiencies. PubMed: 31536340DOI: 10.1021/acs.jmedchem.9b00747 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.65 Å) |
Structure validation
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