2BAG

3D Structure of Torpedo californica acetylcholinesterase complexed with Ganstigmine

2BAG の概要

• エントリーDOI: 10.2210/pdb2bag/pdb
• 関連するPDBエントリー: 1EA5 1GQR 1GQS 1OCE
• 分子名称: Acetylcholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose, PENTAETHYLENE GLYCOL, ... (6 entities in total)
• 機能のキーワード: serine hydrolase, cholinesterase, neurotransmitter cleavage, anti-alzheimer drug, hydrolase
• 由来する生物種: Torpedo californica (Pacific electric ray)
• 細胞内の位置: Isoform H: Cell membrane; Lipid-anchor, GPI- anchor. Isoform T: Cell membrane; Peripheral membrane protein: P04058
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 62777.73

構造登録者

Lamba, D.,Bartolucci, C.,Siotto, M.,Racchi, M.,Villetti, G.,Delcanale, M. (登録日: 2005-10-14, 公開日: 2006-08-29, 最終更新日: 2024-10-23)

主引用文献

Bartolucci, C.,Siotto, M.,Ghidini, E.,Amari, G.,Bolzoni, P.T.,Racchi, M.,Villetti, G.,Delcanale, M.,Lamba, D.
Structural Determinants of Torpedo californica Acetylcholinesterase Inhibition by the Novel and Orally Active Carbamate Based Anti-Alzheimer Drug Ganstigmine (CHF-2819)
J.Med.Chem., 49:5051-5058, 2006

PubMed Abstract: Ganstigmine is an orally active, geneserine derived, carbamate-based acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. The crystal structure of the ganstigmine conjugate with Torpedo californica acetylcholinesterase (TcAChE) has been determined at 2.40 A resolution, and a detailed structure-based analysis of the in vitro and ex vivo anti-AChE activity by ganstigmine and by new geneserine derivatives is presented. The carbamoyl moiety is covalently bound to the active-site serine, whereas the leaving group geneseroline is not retained in the catalytic pocket. The nitrogen atom of the carbamoyl moiety of ganstigmine is engaged in a key hydrogen-bonding interaction with the active site histidine (His440). This result offers an explanation for the inactivation of the catalytic triad and may account for the long duration of action of ganstigmine in vivo. The 3D structure also provides a structural framework for the design of compounds with improved binding affinity and pharmacological properties.

PubMed: 16913695
DOI: 10.1021/jm060293s

実験手法

X-RAY DIFFRACTION (2.4 Å)