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PDBsum entry 6tuz
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Signaling protein
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PDB id
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6tuz
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References listed in PDB file
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Key reference
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Title
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Caffeine inhibits notum activity by binding at the catalytic pocket.
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Authors
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Y.Zhao,
J.Ren,
J.Hillier,
W.Lu,
E.Y.Jones.
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Ref.
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Commun Biol, 2020,
3,
555.
[DOI no: ]
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PubMed id
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Abstract
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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.
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