7nbw

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Crystal structure of PqsR (MvfR) ligand-binding domain in complex with a pyridin agonist

Structural highlights

7nbw is a 1 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 2.28Å
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

A short and divergent route towards new derivatives of 2-(trifluoromethyl)pyridines as potent inverse agonists of the bacterial target PqsR against Pseudomonas aeruginosa (PA) infections is described. This Gram-negative pathogen causes severe nosocomial infections and common antibiotic treatment options are rendered ineffective due to resistance issues. Based on an earlier identified optimized hit, we conducted derivatization and rigidification attempts employing two central building blocks. The western part of the molecule is built up via a 2-(trifluoromethyl)pyridine head group equipped with a terminal alkyne. The eastern section is then introduced through aryliode motifs exploiting Sonogashira as well as Suzuki-type chemistry. Subsequent modification provided quick access to an array of compounds, allowed for deep SAR insights, and enabled to optimize the hit scaffold into a lead structure of nanomolar potency combined with favorable in vitro ADME/T features.

Divergent synthesis and biological evaluation of 2-(trifluoromethyl)pyridines as virulence-attenuating inverse agonists targeting PqsR.,Schutz C, Hodzic A, Hamed M, Abdelsamie AS, Kany AM, Bauer M, Rohrig T, Schmelz S, Scrima A, Blankenfeldt W, Empting M Eur J Med Chem. 2021 Aug 28;226:113797. doi: 10.1016/j.ejmech.2021.113797. PMID:34520957^[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
↑ Schütz C, Hodzic A, Hamed M, Abdelsamie AS, Kany AM, Bauer M, Röhrig T, Schmelz S, Scrima A, Blankenfeldt W, Empting M. Divergent synthesis and biological evaluation of 2-(trifluoromethyl)pyridines as virulence-attenuating inverse agonists targeting PqsR. Eur J Med Chem. 2021 Dec 15;226:113797. PMID:34520957 doi:10.1016/j.ejmech.2021.113797