4xty

Mycobacterium tuberculosis biotin ligase complexed with bisubstrate inhibitor 63 with Fluorine in place of 2'OH

spinqualitylabelsall models 4xty, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4xty is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 44L Related: 4xtu, 4xtv, 4xtw, 4xtx, 4xtz, 4xu0, 4xu1, 4xu2, 4xu3 Activity: [acetyl-CoA-carboxylase_ligase Biotin--[acetyl-CoA-carboxylase] ligase], with EC number 6.3.4.15 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum Publication Abstract from PubMed Mycobacterium tuberculosis (Mtb) responsible for both latent and symptomatic tuberculosis (TB) remains the second leading cause of mortality among infectious diseases worldwide. Mycobacterial biotin protein ligase (MtBPL) is an essential enzyme in Mtb and regulates lipid metabolism through the post-translational biotinylation of acyl coenzyme A carboxylases. We report the synthesis and evaluation of a systematic series of potent nucleoside-based inhibitors of MtBPL that contain modifications to the ribofuranosyl ring of the nucleoside. All compounds were characterized by isothermal titration calorimetry (ITC) and shown to bind potently with KD's below 2 nM. Additionally, we obtained high-resolution co-crystal structures for a majority of the compounds. Despite fairly uniform biochemical potency, the whole-cell Mtb activity varied greatly with minimum inhibitory concentrations (MIC) ranging from 0.78 to >100 microM. Cellular accumulation studies in Mtb showed a nearly 10-fold enhanced accumulation of a C-2'-alpha analog over the corresponding C-2'-beta analog, consistent with their differential whole-cell activity. Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors.,Bockman MR, Kalinda AS, Petrelli R, De la Mora-Rey T, Tiwari D, Liu F, Dawadi S, Nandakumar M, Rhee KY, Schnappinger D, Finzel BC, Aldrich CC J Med Chem. 2015 Aug 24. PMID:26299766 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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