6ttg

Crystal structure of the ATP binding domain of S. aureus GyrB complexed with LMD62

spinqualitylabelsall models 6ttg, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ttg is a 2 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 1.7Å Ligands: CA, CL, GOL, IMD, MPD, NWK Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GYRB_STAAU DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings.[HAMAP-Rule:MF_01898] Publication Abstract from PubMed The rise in multidrug-resistant bacteria defines the need for identification of new antibacterial agents that are less prone to resistance acquisition. Compounds that simultaneously inhibit multiple bacterial targets are more likely to suppress the evolution of target-based resistance than monotargeting compounds. The structurally similar ATP binding sites of DNA gyrase and topoisomerase offer an opportunity to accomplish this goal. Here we present the design and structure-activity relationship analysis of balanced, low nanomolar inhibitors of bacterial DNA gyrase and topoisomerase IV that show potent antibacterial activities against the ESKAPE pathogens. For inhibitor 31c, a crystal structure in complex with Staphylococcus aureus DNA gyrase B was obtained that confirms the mode of action of these compounds. The best inhibitor, 31h, does not show any in vitro cytotoxicity and has excellent potency against Gram-positive (MICs: range, 0.0078-0.0625 mug/mL) and Gram-negative pathogens (MICs: range, 1-2 mug/mL). Furthermore, 31h inhibits GyrB mutants that can develop resistance to other drugs. Based on these data, we expect that structural derivatives of 31h will represent a step toward clinically efficacious multitargeting antimicrobials that are not impacted by existing antimicrobial resistance. New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogens.,Durcik M, Nyerges A, Skok Z, Skledar DG, Trontelj J, Zidar N, Ilas J, Zega A, Cruz CD, Tammela P, Welin M, Kimbung YR, Focht D, Benek O, Revesz T, Draskovits G, Szili PE, Daruka L, Pal C, Kikelj D, Masic LP, Tomasic T Eur J Med Chem. 2021 Mar 5;213:113200. doi: 10.1016/j.ejmech.2021.113200. Epub, 2021 Jan 22. PMID:33524686 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Gyrase 3D Structures

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