5HF9

Crystal structure of human acetylcholinesterase in complex with paraoxon and HI6

5HF9 の概要

• エントリーDOI: 10.2210/pdb5hf9/pdb
• 関連するPDBエントリー: 5HF5 5HF6 5HF8 5HFA
• 分子名称: Acetylcholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, DIETHYL PHOSPHONATE, ... (9 entities in total)
• 機能のキーワード: acetylcholinesterase, 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: 121790.02

構造登録者

Franklin, M.F.,Rudolph, M.J.,Ginter, C.,Cassidy, M.S.,Cheung, J. (登録日: 2016-01-06, 公開日: 2016-06-22, 最終更新日: 2024-10-23)

主引用文献

Franklin, M.C.,Rudolph, M.J.,Ginter, C.,Cassidy, M.S.,Cheung, J.
Structures of paraoxon-inhibited human acetylcholinesterase reveal perturbations of the acyl loop and the dimer interface.
Proteins, 84:1246-1256, 2016

PubMed Abstract: Irreversible inhibition of the essential nervous system enzyme acetylcholinesterase by organophosphate nerve agents and pesticides may quickly lead to death. Oxime reactivators currently used as antidotes are generally less effective against pesticide exposure than nerve agent exposure, and pesticide exposure constitutes the majority of cases of organophosphate poisoning in the world. The current lack of published structural data specific to human acetylcholinesterase organophosphate-inhibited and oxime-bound states hinders development of effective medical treatments. We have solved structures of human acetylcholinesterase in different states in complex with the organophosphate insecticide, paraoxon, and oximes. Reaction with paraoxon results in a highly perturbed acyl loop that causes a narrowing of the gorge in the peripheral site that may impede entry of reactivators. This appears characteristic of acetylcholinesterase inhibition by organophosphate insecticides but not nerve agents. Additional changes seen at the dimer interface are novel and provide further examples of the disruptive effect of paraoxon. Ternary structures of paraoxon-inhibited human acetylcholinesterase in complex with the oximes HI6 and 2-PAM reveals relatively poor positioning for reactivation. This study provides a structural foundation for improved reactivator design for the treatment of organophosphate intoxication. Proteins 2016; 84:1246-1256. © 2016 Wiley Periodicals, Inc.

PubMed: 27191504
DOI: 10.1002/prot.25073

実験手法

X-RAY DIFFRACTION (2.2 Å)