3mcy

Crystal structure of FimH lectin domain bound to biphenyl mannoside meta-methyl ester.

spinqualitylabelsall models 3mcy, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3mcy is a 4 chain structure with sequence from Escherichia coli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.9Å Ligands: CA, CL, GOL, ZH1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q9S497_ECOLX Publication Abstract from PubMed FimH-mediated cellular adhesion to mannosylated proteins is critical in the ability of uropathogenic E. coli (UPEC) to colonize and invade the bladder epithelium during urinary tract infection. We describe the discovery and optimization of potent small-molecule FimH bacterial adhesion antagonists based on alpha-d-mannose 1-position anomeric glycosides using X-ray structure-guided drug design. Optimized biarylmannosides display low nanomolar binding affinity for FimH in a fluorescence polarization assay and submicromolar cellular activity in a hemagglutination (HA) functional cell assay of bacterial adhesion. X-ray crystallography demonstrates that the biphenyl moiety makes several key interactions with the outer surface of FimH including pi-pi interactions with Tyr-48 and an H-bonding electrostatic interaction with the Arg-98/Glu-50 salt bridge. Dimeric analogues linked through the biaryl ring show an impressive 8-fold increase in potency relative to monomeric matched pairs and represent the most potent FimH antagonists identified to date. The FimH antagonists described herein hold great potential for development as novel therapeutics for the effective treatment of urinary tract infections. Structure-Based Drug Design and Optimization of Mannoside Bacterial FimH Antagonists.,Han Z, Pinkner JS, Ford B, Obermann R, Nolan W, Wildman SA, Hobbs D, Ellenberger T, Cusumano CK, Hultgren SJ, Janetka JW J Med Chem. 2010 May 27. PMID:20507142 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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