9hke

Crystal structure of flavin-dependent monooxygenase Tet(X4) in complex with trifluoperazine

spinqualitylabelsall models 9hke, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9hke is a 1 chain structure with sequence from Escherichia coli. 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: FDA, GOL, SO4, TFP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A3T0V9Y5_ECOLX An FAD-requiring monooxygenase active on some tetracycline antibiotic derivatives, which leads to their inactivation. Hydroxylates carbon 11a of tetracycline and some analogs.[HAMAP-Rule:MF_00845] Publication Abstract from PubMed The Tet(X) flavin-dependent monooxygenases enable tetracycline antibiotic resistance by catalysing inactivating hydroxylation, so preventing inhibition of bacterial ribosomes. Tet(X) resistance is growing rapidly, threatening the efficacy of important last-resort tetracyclines such as tigecycline. Tet(X) inhibitors have potential to protect tetracyclines in combination therapies, but their discovery has been hampered by lack of high-throughput assays. We report the development of an efficient fluorescence polarisation Tet(X) binding assay employing a tetramethylrhodamine-glycyl-minocycline conjugate that enables inhibitor discovery. The assay was applied to tetracycline substrates and reported inhibitors, providing insight into their binding modes. Screening of a bioactive molecule library identified novel Tet(X) inhibitors, including psychoactive phenothiazine derivatives and the 5-HT(4) agonist tegaserod, the activities of which were validated by turnover assays. Crystallographic studies of Tet(X4)-inhibitor complexes reveal two new inhibitor binding modes, importantly providing evidence for active site binding of Tet(X) inhibitors that do not share structural similarity with tetracycline substrates. In some cases, potentiation of tigecycline activity was observed in bacteria expressing Tet(X4). The combined results provide non-tetracycline scaffolds for development of potent Tet(X) inhibitors and highlight the need to evaluate the impact of non-antibiotics on antimicrobial resistance. Binding assays enable discovery of Tet(X) inhibitors that combat tetracycline destructase resistance.,Beech MJ, Toma EC, Smith HG, Trush MM, Ang JHJ, Wong MY, Wong CHJ, Ali HS, Butt Z, Goel V, Duarte F, Farley AJM, Walsh TR, Schofield CJ Chem Sci. 2025 May 7. doi: 10.1039/d5sc00964b. PMID:40342919 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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