6TR7

N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide-Notum complex

6TR7 の概要

• エントリーDOI: 10.2210/pdb6tr7/pdb
• 分子名称: Palmitoleoyl-protein carboxylesterase NOTUM, SULFATE ION, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: wnt receptor frizzled8 carbamazepine, oncoprotein
• 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: 45550.04

構造登録者

Zhao, Y.,Jones, E.Y. (登録日: 2019-12-17, 公開日: 2020-01-08, 最終更新日: 2024-11-20)

主引用文献

Zhao, Y.,Ren, J.,Hillier, J.,Jones, M.,Lu, W.,Jones, E.Y.
Structural characterization of melatonin as an inhibitor of the Wnt deacylase Notum.
J. Pineal Res., 68:e12630-e12630, 2020

PubMed Abstract: The hormone melatonin, secreted from the pineal gland, mediates multiple physiological effects including modulation of Wnt/β-catenin signalling. The Wnt palmitoleate lipid modification is essential for its signalling activity, while the carboxylesterase Notum can remove the lipid from Wnt and inactivate it. Notum enzyme inhibition can therefore upregulate Wnt signalling. While searching for Notum inhibitors by crystallographic fragment screening, a hit compound N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide that is structurally similar to melatonin came to our attention. We then soaked melatonin and its precursor N-acetylserotonin into Notum crystals and obtained high-resolution structures (≤1.5 Å) of their complexes. In each of the structures, two compound molecules bind with Notum: one at the enzyme's catalytic pocket, overlapping the space occupied by the acyl tail of the Wnt palmitoleate lipid, and the other at the edge of the pocket opposite the substrate entrance. Although the inhibitory activity of melatonin shown by in vitro enzyme assays is low (IC 75 µmol/L), the structural information reported here provides a basis for the design of potent and brain accessible drugs for neurodegenerative diseases such as Alzheimer's disease, in which upregulation of Wnt signalling may be beneficial.

PubMed: 31876313
DOI: 10.1111/jpi.12630

実験手法

X-RAY DIFFRACTION (1.47 Å)