5n16

First Bromodomain (BD1) from Candida albicans Bdf1 bound to a dibenzothiazepinone (compound 1)

spinqualitylabelsall models 5n16, resolution 1.76Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5n16 is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 8FN, GOL, NI Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [BDF1_CANAL] Transcription factor involved in the expression of a broad class of genes including snRNAs. Required for sporulation and DNA-damage repair. Prevents the spreading of SIR silencing at telomeres and protects histone H4, but not H3, from deacetylation (By similarity). Publication Abstract from PubMed Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies. Here we investigate a chromatin-interacting module, the bromodomain (BD) from the BET family of proteins, as a potential antifungal target in Candida albicans, a major human fungal pathogen. We show that the BET protein Bdf1 is essential in C. albicans and that mutations inactivating its two BDs result in a loss of viability in vitro and decreased virulence in mice. We report small-molecule compounds that inhibit C. albicans Bdf1 with high selectivity over human BDs. Crystal structures of the Bdf1 BDs reveal binding modes for these inhibitors that are sterically incompatible with the human BET-binding pockets. Furthermore, we report a dibenzothiazepinone compound that phenocopies the effects of a Bdf1 BD-inactivating mutation on C. albicans viability. These findings establish BET inhibition as a promising antifungal therapeutic strategy and identify Bdf1 as an antifungal drug target that can be selectively inhibited without antagonizing human BET function. Selective BET bromodomain inhibition as an antifungal therapeutic strategy.,Mietton F, Ferri E, Champleboux M, Zala N, Maubon D, Zhou Y, Harbut M, Spittler D, Garnaud C, Courcon M, Chauvel M, d'Enfert C, Kashemirov BA, Hull M, Cornet M, McKenna CE, Govin J, Petosa C Nat Commun. 2017 May 18;8:15482. doi: 10.1038/ncomms15482. PMID:28516956 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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