6DZQ
The N-terminal domain of PA endonuclease from the influenza H1N1 virus in complex with 3-hydroxy-6-methyl-4-oxo-4H-pyran-2-carboxylic acid
Summary for 6DZQ
| Entry DOI | 10.2210/pdb6dzq/pdb |
| Descriptor | Polymerase acidic protein, MANGANESE (II) ION, 3-hydroxy-6-methyl-4-oxo-4H-pyran-2-carboxylic acid, ... (5 entities in total) |
| Functional Keywords | inhibitor, endonuclease, influenza, pa domain, viral protein, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Influenza A virus (A/California/04/2009(H1N1)) |
| Total number of polymer chains | 1 |
| Total formula weight | 22872.80 |
| Authors | Dick, B.L.,Morrison, C.N.,Cohen, S.M. (deposition date: 2018-07-05, release date: 2018-11-07, Last modification date: 2023-10-11) |
| Primary citation | Credille, C.V.,Dick, B.L.,Morrison, C.N.,Stokes, R.W.,Adamek, R.N.,Wu, N.C.,Wilson, I.A.,Cohen, S.M. Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease. J. Med. Chem., 61:10206-10217, 2018 Cited by PubMed Abstract: Metalloenzymes represent an important target space for drug discovery. A limitation to the early development of metalloenzyme inhibitors has been the lack of established structure-activity relationships (SARs) for molecules that bind the metal ion cofactor(s) of a metalloenzyme. Herein, we employed a bioinorganic perspective to develop an SAR for inhibition of the metalloenzyme influenza RNA polymerase PA endonuclease. The identified trends highlight the importance of the electronics of the metal-binding pharmacophore (MBP), in addition to MBP sterics, for achieving improved inhibition and selectivity. By optimization of the MBPs for PA endonuclease, a class of highly active and selective fragments was developed that displays IC values <50 nM. This SAR led to structurally distinct molecules that also displayed IC values of ∼10 nM, illustrating the utility of a metal-centric development campaign in generating highly active and selective metalloenzyme inhibitors. PubMed: 30351002DOI: 10.1021/acs.jmedchem.8b01363 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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