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| | <StructureSection load='6z5k' size='340' side='right'caption='[[6z5k]], [[Resolution|resolution]] 3.20Å' scene=''> | | <StructureSection load='6z5k' size='340' side='right'caption='[[6z5k]], [[Resolution|resolution]] 3.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6z5k]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseab Pseab]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Z5K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Z5K FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6z5k]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_UCBPP-PA14 Pseudomonas aeruginosa UCBPP-PA14]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Z5K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Z5K FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QAE:6-chloranyl-3-[(2-pentyl-2,3-dihydro-1,3-thiazol-4-yl)methyl]quinazolin-4-one'>QAE</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.201Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[6yz3|6yz3]]</div></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QAE:6-chloranyl-3-[(2-pentyl-2,3-dihydro-1,3-thiazol-4-yl)methyl]quinazolin-4-one'>QAE</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mvfR, PA14_51340 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=208963 PSEAB])</td></tr>
| + | |
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6z5k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6z5k OCA], [https://pdbe.org/6z5k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6z5k RCSB], [https://www.ebi.ac.uk/pdbsum/6z5k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6z5k ProSAT]</span></td></tr> | | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6z5k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6z5k OCA], [https://pdbe.org/6z5k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6z5k RCSB], [https://www.ebi.ac.uk/pdbsum/6z5k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6z5k ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/A0A0H2Z7A6_PSEAB A0A0H2Z7A6_PSEAB] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Pseab]] | + | [[Category: Pseudomonas aeruginosa UCBPP-PA14]] |
| - | [[Category: Emsley, J]] | + | [[Category: Emsley J]] |
| - | [[Category: Richardson, W K]] | + | [[Category: Richardson WK]] |
| - | [[Category: Antagonist]]
| + | |
| - | [[Category: Dna binding protein]]
| + | |
| - | [[Category: Pseudomonas aeruginosa]]
| + | |
| - | [[Category: Quorum sensing]]
| + | |
| Structural highlights
Function
A0A0H2Z7A6_PSEAB
Publication Abstract from PubMed
Rising numbers of cases of multidrug- and extensively drug-resistant Pseudomonas aeruginosa over recent years have created an urgent need for novel therapeutic approaches to cure potentially fatal infections. One such approach is virulence attenuation where anti-virulence compounds, designed to reduce pathogenicity without affording bactericidal effects, are employed to treat infections. P. aeruginosa uses the pqs quorum sensing (QS) system, to coordinate the expression of a large number of virulence determinants as well as bacterial-host interactions and hence represents an excellent anti-virulence target. We report the synthesis and identification of a new series of thiazole-containing quinazolinones capable of inhibiting PqsR, the transcriptional regulator of the pqs QS system. The compounds demonstrated high potency (IC50 < 300 nM) in a whole-cell assay, using a mCTX:PpqsA-lux-based bioreporter for the P. aeruginosa PAO1-L and PA14 strains. Structural evaluation defined the binding modes of four analogues in the ligand-binding domain of PqsR through X-ray crystallography. Further work showed the ability of 6-chloro-3((2-pentylthiazol-4-yl)methyl)quinazolin-4(3H)-one (18) and 6-chloro-3((2-hexylthiazol-4-yl)methyl)quinazolin-4(3H)-one (19) to attenuate production of the PqsR-regulated virulence factor pyocyanin. Compounds 18 and 19 showed a low cytotoxic profile in the A549 human epithelial lung cell line making them suitable candidates for further pre-clinical evaluation.
Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR.,Grossman S, Soukarieh F, Richardson W, Liu R, Mashabi A, Emsley J, Williams P, Camara M, Stocks MJ Eur J Med Chem. 2020 Aug 28;208:112778. doi: 10.1016/j.ejmech.2020.112778. PMID:32927392[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Grossman S, Soukarieh F, Richardson W, Liu R, Mashabi A, Emsley J, Williams P, Camara M, Stocks MJ. Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR. Eur J Med Chem. 2020 Aug 28;208:112778. doi: 10.1016/j.ejmech.2020.112778. PMID:32927392 doi:http://dx.doi.org/10.1016/j.ejmech.2020.112778
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