6RUA

Structure of recombinant human butyrylcholinesterase in complex with a coumarin-based fluorescent probe linked to sulfonamide type inhibitor.

6RUA の概要

• エントリーDOI: 10.2210/pdb6rua/pdb
• 関連するPDBエントリー: 5DYT
• 分子名称: Cholinesterase, diethyl-[6-[[2-[2-[2-[naphthalen-2-ylsulfonyl-[[(3~{R})-1-(phenylmethyl)piperidin-3-yl]methyl]amino]ethoxy]ethoxy]ethylamino]-oxidanyl-methyl]-7-oxidanylidene-1,3,4,4~{a},5,6,8,8~{a}-octahydronaphthalen-2-ylidene]azanium, TRIETHYLENE GLYCOL, ... (12 entities in total)
• 機能のキーワード: human butyrylcholinesterase, insect cell, hydrolase, fluorescent probes, sulfonamide, inhibitor
• 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: 137887.74

構造登録者

Coquelle, N.,Knez, D.,Brus, B.,Gobec, S.,Colletier, J.P. (登録日: 2019-05-27, 公開日: 2020-01-22, 最終更新日: 2024-11-13)

主引用文献

Pajk, S.,Knez, D.,Kosak, U.,Zorovic, M.,Brazzolotto, X.,Coquelle, N.,Nachon, F.,Colletier, J.P.,Zivin, M.,Stojan, J.,Gobec, S.
Development of potent reversible selective inhibitors of butyrylcholinesterase as fluorescent probes.
J Enzyme Inhib Med Chem, 35:498-505, 2020

PubMed Abstract: Brain butyrylcholinesterase (BChE) is an attractive target for drugs designed for the treatment of Alzheimer's disease (AD) in its advanced stages. It also potentially represents a biomarker for progression of this disease. Based on the crystal structure of previously described highly potent, reversible, and selective BChE inhibitors, we have developed the fluorescent probes that are selective towards human BChE. The most promising probes also maintain their inhibition of BChE in the low nanomolar range with high selectivity over acetylcholinesterase. Kinetic studies of probes reveal a reversible mixed inhibition mechanism, with binding of these fluorescent probes to both the free and acylated enzyme. Probes show environment-sensitive emission, and additionally, one of them also shows significant enhancement of fluorescence intensity upon binding to the active site of BChE. Finally, the crystal structures of probes in complex with human BChE are reported, which offer an excellent base for further development of this library of compounds.

PubMed: 31914836
DOI: 10.1080/14756366.2019.1710502

実験手法

X-RAY DIFFRACTION (2.75 Å)