6TV4

CFF-Notum complex

6TV4 の概要

• エントリーDOI: 10.2210/pdb6tv4/pdb
• 分子名称: Palmitoleoyl-protein carboxylesterase NOTUM, SULFATE ION, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: wnt notum inhibitor complex, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 45752.04

構造登録者

Zhao, Y.,Jones, E.Y. (登録日: 2020-01-08, 公開日: 2020-10-28, 最終更新日: 2024-11-20)

主引用文献

Zhao, Y.,Ren, J.,Hillier, J.,Lu, W.,Jones, E.Y.
Caffeine inhibits Notum activity by binding at the catalytic pocket.
Commun Biol, 3:555-555, 2020

PubMed 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 (IC 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 EC of 46 µM. The dissociation constant (K) 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.

PubMed: 33033363
DOI: 10.1038/s42003-020-01286-5

実験手法

X-RAY DIFFRACTION (1.53 Å)