7R2F

Structure of tabun inhibited acetylcholinesterase in complex with 2-((hydroxyimino)methyl)-1-(5-(4-methyl-3-nitrobenzamido)pentyl)pyridinium

7R2F の概要

• エントリーDOI: 10.2210/pdb7r2f/pdb
• 関連するPDBエントリー: 7QYN 7R02 7R0A 7R3C 7R4E
• 分子名称: Acetylcholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose, 4-methyl-3-nitro-~{N}-[(2~{E},4~{E})-5-[2-[(oxidanylamino)methyl]pyridin-1-yl]penta-2,4-dienyl]benzamide, ... (6 entities in total)
• 機能のキーワード: hydrolase, complex, tabun phosphylated, reactivator
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 123050.94

構造登録者

Forsgren, N.,Lindgren, C.,Edvinsson, L.,Linusson, A.,Ekstrom, F. (登録日: 2022-02-04, 公開日: 2022-04-27, 最終更新日: 2024-01-31)

主引用文献

Lindgren, C.,Forsgren, N.,Hoster, N.,Akfur, C.,Artursson, E.,Edvinsson, L.,Svensson, R.,Worek, F.,Ekstrom, F.,Linusson, A.
Broad-Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve-Agent-Inhibited Acetylcholinesterase.
Chemistry, 28:e202200678-e202200678, 2022

PubMed Abstract: Reactivators are vital for the treatment of organophosphorus nerve agent (OPNA) intoxication but new alternatives are needed due to their limited clinical applicability. The toxicity of OPNAs stems from covalent inhibition of the essential enzyme acetylcholinesterase (AChE), which reactivators relieve via a chemical reaction with the inactivated enzyme. Here, we present new strategies and tools for developing reactivators. We discover suitable inhibitor scaffolds by using an activity-independent competition assay to study non-covalent interactions with OPNA-AChEs and transform these inhibitors into broad-spectrum reactivators. Moreover, we identify determinants of reactivation efficiency by analysing reactivation and pre-reactivation kinetics together with structural data. Our results show that new OPNA reactivators can be discovered rationally by exploiting detailed knowledge of the reactivation mechanism of OPNA-inhibited AChE.

PubMed: 35420233
DOI: 10.1002/chem.202200678

実験手法

X-RAY DIFFRACTION (2.3 Å)