6ndl | pdb_00006ndl

Crystal structure of Staphylococcus aureus biotin protein ligase in complex with a sulfonamide inhibitor

spinqualitylabelsall models 6ndl, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ndl is a 1 chain structure with sequence from Staphylococcus aureus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2Å Ligands: BQX, GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q2G258_STAA8 Acts both as a biotin--[acetyl-CoA-carboxylase] ligase and a repressor.[HAMAP-Rule:MF_00978] Publication Abstract from PubMed Here, we report the design, synthesis, and evaluation of a series of inhibitors of Staphylococcus aureus BPL (SaBPL), where the central acyl phosphate of the natural intermediate biotinyl-5'-AMP (1) is replaced by a sulfonamide isostere. Acylsulfamide (6) and amino sulfonylurea (7) showed potent in vitro inhibitory activity (Ki = 0.007 +/- 0.003 and 0.065 +/- 0.03 muM, respectively) and antibacterial activity against S. aureus ATCC49775 with minimum inhibitory concentrations of 0.25 and 4 mug/mL, respectively. Additionally, the bimolecular interactions between the BPL and inhibitors 6 and 7 were defined by X-ray crystallography and molecular dynamics simulations. The high acidity of the sulfonamide linkers of 6 and 7 likely contributes to the enhanced in vitro inhibitory activities by promoting interaction with SaBPL Lys187. Analogues with alkylsulfamide (8), beta-ketosulfonamide (9), and beta-hydroxysulfonamide (10) isosteres were devoid of significant activity. Binding free energy estimation using computational methods suggests deprotonated 6 and 7 to be the best binders, which is consistent with enzyme assay results. Compound 6 was unstable in whole blood, leading to poor pharmacokinetics. Importantly, 7 has a vastly improved pharmacokinetic profile compared to that of 6 presumably due to the enhanced metabolic stability of the sulfonamide linker moiety. Sulfonamide-Based Inhibitors of Biotin Protein Ligase as New Antibiotic Leads.,Lee KJ, Tieu W, Blanco-Rodriguez B, Paparella AS, Yu J, Hayes A, Feng J, Marshall AC, Noll B, Milne R, Cini D, Wilce MCJ, Booker GW, Bruning JB, Polyak SW, Abell AD ACS Chem Biol. 2019 Sep 20;14(9):1990-1997. doi: 10.1021/acschembio.9b00463. Epub, 2019 Aug 21. PMID:31407891 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Biotin Protein Ligase 3D structures

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