6q7u: Difference between revisions

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'''Unreleased structure'''


The entry 6q7u is ON HOLD until Paper Publication
==Crystal structure of PqsR (MvfR) ligand-binding domain in complex with HHQ==
<StructureSection load='6q7u' size='340' side='right'caption='[[6q7u]], [[Resolution|resolution]] 3.14&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6q7u]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Q7U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6Q7U FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HLH:2-heptyl-1~{H}-quinolin-4-one'>HLH</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=6q7u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q7u OCA], [http://pdbe.org/6q7u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6q7u RCSB], [http://www.ebi.ac.uk/pdbsum/6q7u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6q7u ProSAT]</span></td></tr>
</table>
== 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>  
<div style="background-color:#fffaf0;">
== 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.


Authors:  
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<ref>PMID:31709767</ref>


Description:  
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
<div class="pdbe-citations 6q7u" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Blankenfeldt, W]]
[[Category: Witzgall, F]]
[[Category: Xu, N]]
[[Category: Dna binding protein]]
[[Category: Lttr]]
[[Category: Lysr-type transcriptional regulator]]
[[Category: Pseudomonas quinolone signaling system]]
[[Category: Quorum sensing]]

Revision as of 18:34, 20 November 2019

Crystal structure of PqsR (MvfR) ligand-binding domain in complex with HHQCrystal structure of PqsR (MvfR) ligand-binding domain in complex with HHQ

Structural highlights

6q7u is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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

6q7u, resolution 3.14Å

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