6q7v

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Crystal structure of PqsR (MvfR) ligand-binding domain in complex with compound 11

Structural highlights

6q7v is a 2 chain structure with sequence from Pseudomonas aeruginosa PAO1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.56Å
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

↑ 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