Journal article
Caffeine inhibits Notum activity by binding at the catalytic pocket
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, 1.2MB, Terms of use)
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- Publisher copy:
- 10.1038/s42003-020-01286-5
Authors
- Publisher:
- Springer Nature
- Journal:
- Communications Biology More from this journal
- Volume:
- 3
- Issue:
- 1
- Article number:
- 555
- Place of publication:
- England
- Publication date:
- 2020-10-08
- Acceptance date:
- 2020-08-04
- DOI:
- EISSN:
-
2399-3642
- Pmid:
-
33033363
- Language:
-
English
- Keywords:
- Pubs id:
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1136832
- Local pid:
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pubs:1136832
- Deposit date:
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2021-02-27
Terms of use
- Copyright holder:
- Y Zhao et al.
- Copyright date:
- 2020
- Rights statement:
- © The Author(s) 2020. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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