5hs3

Human thymidylate synthase complexed with dUMP and 3-amino-2-benzoyl-4-methylthieno[2,3-b]pyridin-6-ol

spinqualitylabelsall models 5hs3, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5hs3 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.103Å Ligands: KI3, UMP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TYSY_HUMAN Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Publication Abstract from PubMed Target engagement is a critical factor for therapeutic efficacy. Assessment of compound binding to native target proteins in live cells is therefore highly desirable in all stages of drug discovery. We report here the first compound library screen based on biophysical measurements of intracellular target binding, exemplified by human thymidylate synthase (TS). The screen selected accurately for all the tested known drugs acting on TS. We also identified TS inhibitors with novel chemistry and marketed drugs that were not previously known to target TS, including the DNA methyltransferase inhibitor decitabine. By following the cellular uptake and enzymatic conversion of known drugs we correlated the appearance of active metabolites over time with intracellular target engagement. These data distinguished a much slower activation of 5-fluorouracil when compared with nucleoside-based drugs. The approach establishes efficient means to associate drug uptake and activation with target binding during drug discovery. CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil.,Almqvist H, Axelsson H, Jafari R, Dan C, Mateus A, Haraldsson M, Larsson A, Martinez Molina D, Artursson P, Lundback T, Nordlund P Nat Commun. 2016 Mar 24;7:11040. doi: 10.1038/ncomms11040. PMID:27010513 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thymidylate synthase 3D structures

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