Caffeine inhibits Notum activity by binding at the catalytic pocket
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)...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2020
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| _version_ | 1797089177057099776 |
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| author | Zhao, Y Ren, J Hillier, J Lu, W Jones, EY |
| author_facet | Zhao, Y Ren, J Hillier, J Lu, W Jones, EY |
| author_sort | Zhao, Y |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T03:00:40Z |
| format | Journal article |
| id | oxford-uuid:b0dca0e0-72cd-48be-adb8-a8bfdc08c6ce |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:00:40Z |
| publishDate | 2020 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:b0dca0e0-72cd-48be-adb8-a8bfdc08c6ce2022-03-27T03:59:32ZCaffeine inhibits Notum activity by binding at the catalytic pocketJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:b0dca0e0-72cd-48be-adb8-a8bfdc08c6ceEnglishSymplectic ElementsSpringer Nature2020Zhao, YRen, JHillier, JLu, WJones, EYNotum 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. |
| spellingShingle | Zhao, Y Ren, J Hillier, J Lu, W Jones, EY Caffeine inhibits Notum activity by binding at the catalytic pocket |
| title | Caffeine inhibits Notum activity by binding at the catalytic pocket |
| title_full | Caffeine inhibits Notum activity by binding at the catalytic pocket |
| title_fullStr | Caffeine inhibits Notum activity by binding at the catalytic pocket |
| title_full_unstemmed | Caffeine inhibits Notum activity by binding at the catalytic pocket |
| title_short | Caffeine inhibits Notum activity by binding at the catalytic pocket |
| title_sort | caffeine inhibits notum activity by binding at the catalytic pocket |
| work_keys_str_mv | AT zhaoy caffeineinhibitsnotumactivitybybindingatthecatalyticpocket AT renj caffeineinhibitsnotumactivitybybindingatthecatalyticpocket AT hillierj caffeineinhibitsnotumactivitybybindingatthecatalyticpocket AT luw caffeineinhibitsnotumactivitybybindingatthecatalyticpocket AT jonesey caffeineinhibitsnotumactivitybybindingatthecatalyticpocket |