3rux | pdb_00003rux

Crystal structure of biotin-protein ligase BirA from Mycobacterium tuberculosis in complex with an acylsulfamide bisubstrate inhibitor

spinqualitylabelsall models 3rux, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3rux is a 2 chain structure with sequence from "bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BS5 Related: 2cgh, 3l1a, 3l2z Gene: birA, MT3379, Rv3279c ("Bacillus tuberculosis" (Zopf 1883) Klein 1884) Activity: [acetyl-CoA-carboxylase_ligase Biotin--[acetyl-CoA-carboxylase] ligase], with EC number 6.3.4.15 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The mycobacterial biotin protein ligase (MtBPL) globally regulates lipid metabolism in Mtb through the posttranslational biotinylation of acyl coenzyme A carboxylases involved in lipid biosynthesis that catalyze the first step in fatty acid biosynthesis and pyruvate coenzyme A carboxylase, a gluconeogenic enzyme vital for lipid catabolism. Here we describe the design, development, and evaluation of a rationally designed bisubstrate inhibitor of MtBPL. This inhibitor displays potent subnanomolar enzyme inhibition and antitubercular activity against multidrug resistant and extensively drug resistant Mtb strains. We show that the inhibitor decreases in vivo protein biotinylation of key enzymes involved in fatty acid biosynthesis and that the antibacterial activity is MtBPL dependent. Additionally, the gene encoding BPL was found to be essential in M. smegmatis. Finally, the X-ray cocrystal structure of inhibitor bound MtBPL was solved providing detailed insight for further structure-activity analysis. Collectively, these data suggest that MtBPL is a promising target for further antitubercular therapeutic development. Bisubstrate Adenylation Inhibitors of Biotin Protein Ligase from Mycobacterium tuberculosis.,Duckworth BP, Geders TW, Tiwari D, Boshoff HI, Sibbald PA, Barry CE 3rd, Schnappinger D, Finzel BC, Aldrich CC Chem Biol. 2011 Nov 23;18(11):1432-41. PMID:22118677 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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