6nlg

1.50 A resolution structure of BfrB (C89S/K96C) from Pseudomonas aeruginosa in complex with a small molecule fragment (analog 1)

spinqualitylabelsall models 6nlg, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6nlg is a 4 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 1.5Å Ligands: HEM, K, KT7, MPD, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q9HY79_PSEAE Iron-storage protein (By similarity). Iron-storage protein, whose ferroxidase center binds Fe(2+) ions, oxidizes them by dioxygen to Fe(3+), and participates in the subsequent Fe(3+) oxide mineral core formation within the central cavity of the protein complex (By similarity).[PIRNR:PIRNR002560] Publication Abstract from PubMed The iron storage protein bacterioferritin (BfrB) is central to bacterial iron homeostasis. The mobilization of iron from BfrB, which requires binding by a cognate ferredoxin (Bfd), is essential to the regulation of cytosolic iron levels in P. aeruginosa. This paper describes the structure-guided development of small molecule inhibitors of the BfrB-Bfd protein-protein interaction. The process was initiated by screening a fragment library and followed by obtaining the structure of a fragment hit bound to BfrB. The structural insights were used to develop a series of 4-(benzylamino)- and 4-((3-phenylpropyl)amino)-isoindoline-1,3-dione analogs that selectively bind BfrB at the Bfd binding site. Challenging P. aeruginosa cells with the 4-substituted isoindoline analogs revealed a dose-dependent growth phenotype. Further investigation determined that the analogs elicit a pyoverdin hyperproduction phenotype that is consistent with blockade of the BfrB-Bfd interaction and ensuing irreversible accumulation of iron in BfrB, with concomitant depletion of iron in the cytosol. The irreversible accumulation of iron in BfrB prompted by the 4-substituted isoindoline analogs was confirmed by visualization of BfrB-iron in P. aeruginosa cell lysates separated on native PAGE gels and stained for iron with Ferene S. Challenging P. aeruginosa cultures with a combination of commercial fluoroquinolone and our isoindoline analogs results in significantly lower cell survival relative to treatment with either antibiotic or analog alone. Collectively, these findings furnish proof of concept for the usefulness of small molecule probes designed to dysregulate bacterial iron homeostasis by targeting a protein-protein interaction pivotal for iron storage in the bacterial cell. Small Molecule Inhibitors of the BfrB-Bfd Interaction Decrease Pseudomonas aeruginosa Fitness and Potentiate Fluoroquinolone Activity.,Punchi Hewage AND, Yao H, Nammalwar B, Gnanasekaran KK, Lovell S, Bunce RA, Eshelman K, Phaniraj SM, Lee MM, Peterson BR, Battaile KP, Reitz AB, Rivera M J Am Chem Soc. 2019 May 9. doi: 10.1021/jacs.9b00394. PMID:31038945 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ferritin 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA