8DT7

X-ray structure of human acetylcholinesterase in complex with oxime MMB4 (hAChE-MMB4)

8DT7 の概要

• エントリーDOI: 10.2210/pdb8dt7/pdb
• 関連するPDBエントリー: 8DT4
• 分子名称: Acetylcholinesterase, 1,1'-methylenebis{4-[(E)-(hydroxyimino)methyl]pyridin-1-ium}, NITRATE ION, ... (5 entities in total)
• 機能のキーワード: acetylcholine hydrolysis, oxime reactivator, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 121584.89

構造登録者

Kovalevsky, A.Y.,Gerlits, O.,Radic, Z. (登録日: 2022-07-25, 公開日: 2022-11-02, 最終更新日: 2024-11-06)

主引用文献

Gerlits, O.,Fajer, M.,Cheng, X.,Blumenthal, D.K.,Radic, Z.,Kovalevsky, A.
Structural and dynamic effects of paraoxon binding to human acetylcholinesterase by X-ray crystallography and inelastic neutron scattering.
Structure, 30:1538-1549.e3, 2022

PubMed Abstract: Organophosphorus (OP) compounds, including nerve agents and some pesticides, covalently bind to the catalytic serine of human acetylcholinesterase (hAChE), thereby inhibiting acetylcholine hydrolysis necessary for efficient neurotransmission. Oxime antidotes can reactivate the OP-conjugated hAChE, but reactivation efficiency can be low for pesticides, such as paraoxon (POX). Understanding structural and dynamic determinants of OP inhibition and reactivation can provide insights to design improved reactivators. Here, X-ray structures of hAChE with unaged POX, with POX and oximes MMB4 and RS170B, and with MMB4 are reported. A significant conformational distortion of the acyl loop was observed upon POX binding, being partially restored to the native conformation by oximes. Neutron vibrational spectroscopy combined with molecular dynamics simulations showed that picosecond vibrational dynamics of the acyl loop soften in the ∼20-50 cm frequency range. The acyl loop structural perturbations may be correlated with its picosecond vibrational dynamics to yield more comprehensive template for structure-based reactivator design.

PubMed: 36265484
DOI: 10.1016/j.str.2022.09.006

実験手法

X-RAY DIFFRACTION (2.207 Å)