7B37

Notum complex with ARUK3003718

7B37 の概要

• エントリーDOI: 10.2210/pdb7b37/pdb
• 分子名称: Palmitoleoyl-protein carboxylesterase NOTUM, 2-acetamido-2-deoxy-beta-D-glucopyranose, SULFATE ION, ... (7 entities in total)
• 機能のキーワード: notum inhibitor, hydrolase
• 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: 44750.38

構造登録者

Zhao, Y.,Jone, E.Y. (登録日: 2020-11-28, 公開日: 2021-08-04, 最終更新日: 2024-11-13)

主引用文献

Zhao, Y.,Svensson, F.,Steadman, D.,Frew, S.,Monaghan, A.,Bictash, M.,Moreira, T.,Chalk, R.,Lu, W.,Fish, P.V.,Jones, E.Y.
Structural Insights into Notum Covalent Inhibition.
J.Med.Chem., 64:11354-11363, 2021

PubMed Abstract: The carboxylesterase Notum hydrolyzes a palmitoleate moiety from Wingless/Integrated(Wnt) ligands and deactivates Wnt signaling. Notum inhibitors can restore Wnt signaling which may be of therapeutic benefit for pathologies such as osteoporosis and Alzheimer's disease. We report the identification of a novel class of covalent Notum inhibitors, 4-(indolin-1-yl)-4-oxobutanoate esters. High-resolution crystal structures of the Notum inhibitor complexes reveal a common covalent adduct formed between the nucleophile serine-232 and hydrolyzed butyric esters. The covalent interaction in solution was confirmed by mass spectrometry analysis. Inhibitory potencies vary depending on the warheads used. Mechanistically, the resulting acyl-enzyme intermediate carbonyl atom is positioned at an unfavorable angle for the approach of the active site water, which, combined with strong hydrophobic interactions with the enzyme pocket residues, hinders the intermediate from being further processed and results in covalent inhibition. These insights into Notum catalytic inhibition may guide development of more potent Notum inhibitors.

PubMed: 34292747
DOI: 10.1021/acs.jmedchem.1c00701

実験手法

X-RAY DIFFRACTION (1.34 Å)