6tuz

Theophylline-Notum complex

spinqualitylabelsall models 6tuz, resolution 1.24Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.24Å Ligands: DMS, EDO, NAG, SO4, TEP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Notum inhibits Wnt signalling via enzymatic delipidation of Wnt ligands. Restoration of Wnt signalling by small molecule inhibition of Notum may be of therapeutic benefit in a number of pathologies including Alzheimer's disease. Here we report Notum activity can be inhibited by caffeine (IC50 19 microM), but not by demethylated caffeine metabolites: paraxanthine, theobromine and theophylline. Cellular luciferase assays show Notum-suppressed Wnt3a function can be restored by caffeine with an EC50 of 46 microM. The dissociation constant (Kd) between Notum and caffeine is 85 microM as measured by surface plasmon resonance. High-resolution crystal structures of Notum complexes with caffeine and its minor metabolite theophylline show both compounds bind at the centre of the enzymatic pocket, overlapping the position of the natural substrate palmitoleic lipid, but using different binding modes. The structural information reported here may be of relevance for the design of more potent brain-accessible Notum inhibitors. Caffeine inhibits Notum activity by binding at the catalytic pocket.,Zhao Y, Ren J, Hillier J, Lu W, Jones EY Commun Biol. 2020 Oct 8;3(1):555. doi: 10.1038/s42003-020-01286-5. PMID:33033363 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Carboxylesterase 3D structures

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