7P1N

Crystal structure of human acetylcholinesterase in complex with (2R,3R,4S,5S,6R)-2-{4-[1-(4-{5-hydroxy-6-[(E)-(hydroxyimino)methyl]pyridin-2-yl}butyl)-1H-1,2,3-triazol-4-yl]butoxy}-6-(hydroxymethyl)oxane-3,4,5-triol oxime

これはPDB形式変換不可エントリーです。

7P1N の概要

• エントリーDOI: 10.2210/pdb7p1n/pdb
• 分子名称: Acetylcholinesterase, MAGNESIUM ION, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total)
• 機能のキーワード: cholinesterase, glucoconjugated oximes, hydrolase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 123861.23

構造登録者

Da Silva, O.,Dias, J.,Nachon, F. (登録日: 2021-07-02, 公開日: 2022-06-08, 最終更新日: 2024-10-16)

主引用文献

Da Silva, O.,Probst, N.,Landry, C.,Hanak, A.S.,Warnault, P.,Coisne, C.,Calas, A.G.,Gosselet, F.,Courageux, C.,Gastellier, A.J.,Trancart, M.,Baati, R.,Dehouck, M.P.,Jean, L.,Nachon, F.,Renard, P.Y.,Dias, J.
A New Class of Bi- and Trifunctional Sugar Oximes as Antidotes against Organophosphorus Poisoning.
J.Med.Chem., 65:4649-4666, 2022

PubMed Abstract: Recent events demonstrated that organophosphorus nerve agents are a serious threat for civilian and military populations. The current therapy includes a pyridinium aldoxime reactivator to restore the enzymatic activity of acetylcholinesterase located in the central nervous system and neuro-muscular junctions. One major drawback of these charged acetylcholinesterase reactivators is their poor ability to cross the blood-brain barrier. In this study, we propose to evaluate glucoconjugated oximes devoid of permanent charge as potential central nervous system reactivators. We determined their reactivation efficacy on inhibited human acetylcholinesterase, the crystal structure of two compounds in complex with the enzyme, their protective index on intoxicated mice, and their pharmacokinetics. We then evaluated their endothelial permeability coefficients with a human model. This study shed light on the structural restrains of new sugar oximes designed to reach the central nervous system through the glucose transporter located at the blood-brain barrier.

PubMed: 35255209
DOI: 10.1021/acs.jmedchem.1c01748

実験手法

X-RAY DIFFRACTION (2.95 Å)