5mmn

E. coli DNA Gyrase B 24 kDa ATPase domain in complex with 1-ethyl-3-[8-methyl-5-(2-methyl-pyridin-4-yl)-isoquinolin-3-yl]-urea

spinqualitylabelsall models 5mmn, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5mmn is a 1 chain structure with sequence from Escherichia coli O157:H7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.9Å Ligands: O54 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GYRB_ECO57 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 Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chemical series, and efforts toward its minimization are reported. Discovery and Optimization of Isoquinoline Ethyl Ureas as Antibacterial Agents.,Panchaud P, Bruyere T, Blumstein AC, Bur D, Chambovey A, Ertel EA, Gude M, Hubschwerlen C, Jacob L, Kimmerlin T, Pfeifer T, Prade L, Seiler P, Ritz D, Rueedi G J Med Chem. 2017 Apr 24. doi: 10.1021/acs.jmedchem.6b01834. PMID:28406299 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Gyrase 3D Structures

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