5cty
Crystal structure of the ATP binding domain of S. aureus GyrB complexed with a fragmentCrystal structure of the ATP binding domain of S. aureus GyrB complexed with a fragment
Structural highlights
FunctionGYRB_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 PubMedInhibitors of the ATPase function of bacterial DNA gyrase, located in the GyrB subunit and its related ParE subunit in topoisomerase IV, have demonstrated antibacterial activity. In this study we describe an NMR fragment-based screening effort targeting Staphylococcus aureus GyrB that identified several attractive and novel starting points with good ligand efficiency. Fragment hits were further characterized using NMR binding studies against full-length S. aureus GyrB and Escherichia coli ParE. X-ray co-crystal structures of select fragment hits confirmed binding and suggested a path for medicinal chemistry optimization. The identification, characterization, and elaboration of one of these fragment series to a 0.265muM inhibitor is described herein. Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB.,Mesleh MF, Cross JB, Zhang J, Kahmann J, Andersen OA, Barker J, Cheng RK, Felicetti B, Wood M, Hadfield AT, Scheich C, Moy TI, Yang Q, Shotwell J, Nguyen K, Lippa B, Dolle R, Ryan MD Bioorg Med Chem Lett. 2016 Jan 6. pii: S0960-894X(16)30009-9. doi:, 10.1016/j.bmcl.2016.01.009. PMID:26786695[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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