5f3f

Crystal structure of para-biphenyl-2-methyl-3'-methyl amide mannoside bound to FimH lectin domain

spinqualitylabelsall models 5f3f, resolution 1.76Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5f3f is a 1 chain structure with sequence from Escherichia coli J96. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.76Å Ligands: 5US Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function FIMH_ECOLI Involved in regulation of length and mediation of adhesion of type 1 fimbriae (but not necessary for the production of fimbriae). Adhesin responsible for the binding to D-mannose. It is laterally positioned at intervals in the structure of the type 1 fimbriae. In order to integrate FimH in the fimbriae FimF and FimG are needed. Publication Abstract from PubMed Gram-negative uropathogenic Escherichia coli (UPEC) bacteria are a causative pathogen of urinary tract infections (UTIs). Previously developed antivirulence inhibitors of the type 1 pilus adhesin, FimH, demonstrated oral activity in animal models of UTI but were found to have limited compound exposure due to the metabolic instability of the O-glycosidic bond (O-mannosides). Herein, we disclose that compounds having the O-glycosidic bond replaced with carbon linkages had improved stability and inhibitory activity against FimH. We report on the design, synthesis, and in vivo evaluation of this promising new class of carbon-linked C-mannosides that show improved pharmacokinetic (PK) properties relative to O-mannosides. Interestingly, we found that FimH binding is stereospecifically modulated by hydroxyl substitution on the methylene linker, where the R-hydroxy isomer has a 60-fold increase in potency. This new class of C-mannoside antagonists have significantly increased compound exposure and, as a result, enhanced efficacy in mouse models of acute and chronic UTI. Antivirulence C-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary Tract Infections.,Mydock-McGrane L, Cusumano Z, Han Z, Binkley J, Kostakioti M, Hannan T, Pinkner JS, Klein R, Kalas V, Crowley J, Rath NP, Hultgren SJ, Janetka JW J Med Chem. 2016 Oct 27;59(20):9390-9408. doi: 10.1021/acs.jmedchem.6b00948. Epub , 2016 Oct 14. PMID:27689912 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Adhesin 3D structures

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