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| | <StructureSection load='6q7v' size='340' side='right'caption='[[6q7v]], [[Resolution|resolution]] 2.56Å' scene=''> | | <StructureSection load='6q7v' size='340' side='right'caption='[[6q7v]], [[Resolution|resolution]] 2.56Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6q7v]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Pseae Pseae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Q7V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6Q7V FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6q7v]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_PAO1 Pseudomonas aeruginosa PAO1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Q7V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Q7V FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HLK:~{N}4-[(4-fluorophenyl)methyl]-6-(trifluoromethyl)pyridine-2,4-diamine'>HLK</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]] 2.56Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mvfR, PA1003 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=208964 PSEAE])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HLK:~{N}4-[(4-fluorophenyl)methyl]-6-(trifluoromethyl)pyridine-2,4-diamine'>HLK</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6q7v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q7v OCA], [http://pdbe.org/6q7v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6q7v RCSB], [http://www.ebi.ac.uk/pdbsum/6q7v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6q7v 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=6q7v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q7v OCA], [https://pdbe.org/6q7v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6q7v RCSB], [https://www.ebi.ac.uk/pdbsum/6q7v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6q7v ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MVFR_PSEAE MVFR_PSEAE]] Transcription regulator that plays a critical role in virulence by positively regulating the expression of multiple quorum sensing (QS)-regulated virulence factors, genes involved in protein secretion, translation, response to oxidative stress and the phnAB operon (PubMed:11724939, PubMed:27678057, PubMed:17083468). At the stationary phase, negatively autoregulates its function through cleavage and translocation to the extracellular space (PubMed:11724939).<ref>PMID:11724939</ref> <ref>PMID:17083468</ref> <ref>PMID:27678057</ref> | + | [https://www.uniprot.org/uniprot/MVFR_PSEAE MVFR_PSEAE] Transcription regulator that plays a critical role in virulence by positively regulating the expression of multiple quorum sensing (QS)-regulated virulence factors, genes involved in protein secretion, translation, response to oxidative stress and the phnAB operon (PubMed:11724939, PubMed:27678057, PubMed:17083468). At the stationary phase, negatively autoregulates its function through cleavage and translocation to the extracellular space (PubMed:11724939).<ref>PMID:11724939</ref> <ref>PMID:17083468</ref> <ref>PMID:27678057</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6q7v" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6q7v" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Transcriptional activator 3D structures|Transcriptional activator 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Pseae]] | + | [[Category: Pseudomonas aeruginosa PAO1]] |
| - | [[Category: Blankenfeldt, W]] | + | [[Category: Blankenfeldt W]] |
| - | [[Category: Witzgall, F]] | + | [[Category: Witzgall F]] |
| - | [[Category: Dna binding protein]]
| + | |
| - | [[Category: Lttr]]
| + | |
| - | [[Category: Lysr-type transcriptional regulator]]
| + | |
| - | [[Category: Pseudomonas quinolone signaling system]]
| + | |
| - | [[Category: Quorum sensing]]
| + | |
| Structural highlights
Function
MVFR_PSEAE Transcription regulator that plays a critical role in virulence by positively regulating the expression of multiple quorum sensing (QS)-regulated virulence factors, genes involved in protein secretion, translation, response to oxidative stress and the phnAB operon (PubMed:11724939, PubMed:27678057, PubMed:17083468). At the stationary phase, negatively autoregulates its function through cleavage and translocation to the extracellular space (PubMed:11724939).[1] [2] [3]
Publication Abstract from PubMed
Hit-to-lead optimization is a critical phase in drug discovery. Herein, we report on the fragment-based discovery and optimization of 2-amino pyridine derivatives as a novel lead-like structure for the treatment of the dangerous opportunistic pathogen Pseudomonas aeruginosa . We pursue an innovative treatment strategy by interfering with the Pseudomonas Quinolone Signal (PQS) Quorum Sensing (QS) system leading to an abolishment of bacterial pathogenicity. Our compounds act on the PQS receptor (PqsR), a key transcription factor controlling the expression of various pathogenicity determinants. In this target-driven approach, we made use of biophysical screening via surface plasmon resonance (SPR) followed by isothermal titration calorimetry (ITC)-enabled enthalpic efficiency (EE) evaluation. Hit optimization then involved growth vector identification and exploitation. Astonishingly, the latter was successfully achieved by introducing flexible linkers rather than rigid motifs leading to a boost in activity on the target receptor and anti-virulence potency.
Flexible Fragment Growing Boosts Potency of Quorum Sensing Inhibitors against Pseudomonas aeruginosa Virulence.,Zender M, Witzgall F, Kiefer AF, Kirsch B, Maurer CK, Kany AM, Xu N, Schmelz S, Borger C, Blankenfeldt W, Empting M ChemMedChem. 2019 Nov 11. doi: 10.1002/cmdc.201900621. PMID:31709767[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Cao H, Krishnan G, Goumnerov B, Tsongalis J, Tompkins R, Rahme LG. A quorum sensing-associated virulence gene of Pseudomonas aeruginosa encodes a LysR-like transcription regulator with a unique self-regulatory mechanism. Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14613-8. doi: 10.1073/pnas.251465298., Epub 2001 Nov 27. PMID:11724939 doi:http://dx.doi.org/10.1073/pnas.251465298
- ↑ Xiao G, Deziel E, He J, Lepine F, Lesic B, Castonguay MH, Milot S, Tampakaki AP, Stachel SE, Rahme LG. MvfR, a key Pseudomonas aeruginosa pathogenicity LTTR-class regulatory protein, has dual ligands. Mol Microbiol. 2006 Dec;62(6):1689-99. doi: 10.1111/j.1365-2958.2006.05462.x. PMID:17083468 doi:http://dx.doi.org/10.1111/j.1365-2958.2006.05462.x
- ↑ Maura D, Hazan R, Kitao T, Ballok AE, Rahme LG. Evidence for Direct Control of Virulence and Defense Gene Circuits by the Pseudomonas aeruginosa Quorum Sensing Regulator, MvfR. Sci Rep. 2016 Sep 28;6:34083. doi: 10.1038/srep34083. PMID:27678057 doi:http://dx.doi.org/10.1038/srep34083
- ↑ Zender M, Witzgall F, Kiefer AF, Kirsch B, Maurer CK, Kany AM, Xu N, Schmelz S, Borger C, Blankenfeldt W, Empting M. Flexible Fragment Growing Boosts Potency of Quorum Sensing Inhibitors against Pseudomonas aeruginosa Virulence. ChemMedChem. 2019 Nov 11. doi: 10.1002/cmdc.201900621. PMID:31709767 doi:http://dx.doi.org/10.1002/cmdc.201900621
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