2YBU

Crystal structure of human acidic chitinase in complex with bisdionin F

2YBU の概要

• エントリーDOI: 10.2210/pdb2ybu/pdb
• 関連するPDBエントリー: 2YBT
• 分子名称: ACIDIC MAMMALIAN CHITINASE, GLYCEROL, 3,7-DIMETHYL-1-[3-(3-METHYL-2,6-DIOXO-9H-PURIN-1-YL)PROPYL]PURINE-2,6-DIONE, ... (4 entities in total)
• 機能のキーワード: hydrolase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Isoform 1: Secreted. Isoform 2: Cytoplasm. Isoform 3: Cytoplasm: Q9BZP6
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 260948.67

構造登録者

Sutherland, T.E.,Andersen, O.A.,Betou, M.,Eggleston, I.M.,Maizels, R.M.,van Aalten, D.,Allen, J.E. (登録日: 2011-03-10, 公開日: 2011-06-08, 最終更新日: 2024-11-06)

主引用文献

Sutherland, T.E.,Andersen, O.A.,Betou, M.,Eggleston, I.M.,Maizels, R.M.,van Aalten, D.,Allen, J.E.
Analyzing airway inflammation with chemical biology: dissection of acidic mammalian chitinase function with a selective drug-like inhibitor.
Chem. Biol., 18:569-579, 2011

PubMed Abstract: Acidic mammalian chitinase (AMCase) is produced in the lung during allergic inflammation and asthma, and inhibition of enzymatic activity has been considered as a therapeutic strategy. However, most chitinase inhibitors are nonselective, additionally inhibiting chitotriosidase activity. Here, we describe bisdionin F, a competitive AMCase inhibitor with 20-fold selectivity for AMCase over chitotriosidase, designed by utilizing the AMCase crystal structure and dicaffeine scaffold. In a murine model of allergic inflammation, bisdionin F-treatment attenuated chitinase activity and alleviated the primary features of allergic inflammation including eosinophilia. However, selective AMCase inhibition by bisdionin F also caused dramatic and unexpected neutrophilia in the lungs. This class of inhibitor will be a powerful tool to dissect the functions of mammalian chitinases in disease and represents a synthetically accessible scaffold to optimize inhibitory properties in terms of airway inflammation.

PubMed: 21609838
DOI: 10.1016/j.chembiol.2011.02.017

実験手法

X-RAY DIFFRACTION (2.25 Å)