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E. coli GyrB ATPase domain in complex with Naringenin
Structural highlights
FunctionGYRB_ECOLI 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.[1] [2] [3] Publication Abstract from PubMedDNA gyrase is an essential DNA topoisomerase that exists only in bacteria. Since novobiocin was withdrawn from the market, new scaffolds and new mechanistic GyrB inhibitors are urgently needed. In this study, we employed fragment screening and X-ray crystallography to identify new building blocks, as well as their binding mechanisms, to support the discovery of new GyrB inhibitors. In total, 84 of the 618 chemical fragments were shown to either thermally stabilize the ATPase domain of Escherichia coli GyrB or inhibit the ATPase activity of E. coli gyrase. Among them, the IC50 values of fragments 10 and 23 were determined to be 605.3 muM and 446.2 muM, respectively. Cocrystal structures of the GyrB ATPase domain with twelve fragment hits were successfully determined at a high resolution. All twelve fragments were deeply inserted in the pocket and formed H-bonds with Asp73 and Thr165, and six fragments formed an additional H-bond with the backbone oxygen of Val71. Fragment screening further highlighted the capability of Asp73, Thr165 and Val71 to bind chemicals and provided diverse building blocks for the design of GyrB inhibitors. Identification of new building blocks by fragment screening for discovering GyrB inhibitors.,Yu Y, Guo J, Cai Z, Ju Y, Xu J, Gu Q, Zhou H Bioorg Chem. 2021 Sep;114:105040. doi: 10.1016/j.bioorg.2021.105040. Epub 2021, May 31. PMID:34098257[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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