9f8h | pdb_00009f8h

Crystal Structure of PhzA/B from Burkholderia cepacia R18194 in complex with Raloxifene

spinqualitylabelsall models 9f8h, resolution 1.47Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9f8h is a 2 chain structure with sequence from Burkholderia lata. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.47Å Ligands: EDO, GOL, RAL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q396C9_BURL3 Publication Abstract from PubMed The human pathogen Pseudomonas aeruginosa is particularly notorious for its multiple resistance mechanisms. A new concept for anti-infectives is the "pathoblocker" approach, which targets virulence factors to disarm rather than kill pathogens and thus attenuates the development of resistance. Based on the estrogen receptor modulator raloxifene, which had previously been identified as a potential biosynthesis inhibitor of the virulence factor pyocyanin via in silico screening, analogues have been developed as pathoblockers against P. aeruginosa. These compounds reduce the production of pyocyanin by binding to the phenazine biosynthesis enzyme PhzB. Structure-activity relationships (SAR) were explored using nano differential scanning fluorimetry, isothermal titration calorimetry, and 12 X-ray cocrystal structures. Compared to raloxifene, congener 20c shows a 60-fold lower affinity for the human estrogen receptor with a 15-fold increase in pyocyanin inhibitory activity. The comprehensive structural information gathered in this study paves the way for the development of improved pathoblockers with increased potency and selectivity. From Bones to Bugs: Structure-Based Development of Raloxifene-Derived Pathoblockers That Inhibit Pyocyanin Production in Pseudomonas aeruginosa.,Thiemann M, Zimmermann M, Diederich C, Zhan H, Lebedev M, Pletz J, Baumgarten J, Handke M, Musken M, Breinbauer R, Krasteva-Christ G, Zanin E, Empting M, Schiedel M, Kunick C, Blankenfeldt W J Med Chem. 2025 Apr 10;68(7):7390-7420. doi: 10.1021/acs.jmedchem.4c03065. Epub , 2025 Mar 29. PMID:40156840 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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