6T9P

Human Butyrylcholinesterase in complex with 2-(N-hydroxyimino)-N-[(1R)-3-{4-[(2-methyl-1H-imidazol-1-yl)methyl]-1H-1,2,3-triazol-1-yl}-1- phenylpropyl]acetamide

6T9P の概要

• エントリーDOI: 10.2210/pdb6t9p/pdb
• 分子名称: Cholinesterase, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[1-deoxy-alpha-D-tagatopyranose-(2-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• 機能のキーワード: butyrylcholinesterase, complex, oxime, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 62334.00

構造登録者

Brazzolotto, X.,Sinko, G.,Marakovic, N.,Knezevic, A. (登録日: 2019-10-28, 公開日: 2020-07-15, 最終更新日: 2024-11-20)

主引用文献

Marakovic, N.,Knezevic, A.,Roncevic, I.,Brazzolotto, X.,Kovarik, Z.,Sinko, G.
Enantioseparation, in vitro testing, and structural characterization of triple-binding reactivators of organophosphate-inhibited cholinesterases.
Biochem.J., 477:2771-2790, 2020

PubMed Abstract: The enantiomers of racemic 2-hydroxyimino-N-(azidophenylpropyl)acetamide-derived triple-binding oxime reactivators were separated, and tested for inhibition and reactivation of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibited with tabun (GA), cyclosarin (GF), sarin (GB), and VX. Both enzymes showed the greatest affinity toward the methylimidazole derivative (III) of 2-hydroxyimino-N-(azidophenylpropyl)acetamide (I). The crystal structure was determined for the complex of oxime III within human BChE, confirming that all three binding groups interacted with active site residues. In the case of BChE inhibited by GF, oximes I (kr = 207 M-1 min-1) and III (kr = 213 M-1 min-1) showed better reactivation efficiency than the reference oxime 2-PAM. Finally, the key mechanistic steps in the reactivation of GF-inhibited BChE with oxime III were modeled using the PM7R6 method, stressing the importance of proton transfer from Nε of His438 to Oγ of Ser203 for achieving successful reactivation.

PubMed: 32639532
DOI: 10.1042/BCJ20200192

実験手法

X-RAY DIFFRACTION (2.7 Å)