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Caffeine inhibits Notum activity by binding at the catalytic pocket

DOI: 10.1038/s42003-020-01286-5 DOI Help

Authors: Yuguang Zhao (Wellcome Centre for Human Genetics, University of Oxford) , Jingshan Ren (Wellcome Centre for Human Genetics, University of Oxford) , James Hillier (Wellcome Centre for Human Genetics, University of Oxford) , Weixian Lu (Wellcome Centre for Human Genetics, University of Oxford) , Edith Yvonne Jones (Wellcome Centre for Human Genetics, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Communications Biology , VOL 3

State: Published (Approved)
Published: October 2020
Diamond Proposal Number(s): 14744

Open Access Open Access

Abstract: 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 µM), 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 µM. The dissociation constant (Kd) between Notum and caffeine is 85 µM 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.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

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s42003-020-01286-5.pdf