5TYL

alpha-esterase-7 in complex with naphthalen-2-ylboronic acid

5TYL の概要

• エントリーDOI: 10.2210/pdb5tyl/pdb
• 関連するPDBエントリー: 5TYJ 5TYK 5TYM 5TYN 5TYO 5TYP
• 分子名称: Carboxylic ester hydrolase, naphthalen-2-ylboronic acid (3 entities in total)
• 機能のキーワード: carboxylesterase, insecticide resistance, covalent inhibitor, organophosphate, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Lucilia cuprina (Green bottle fly)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 66560.82

構造登録者

Correy, G.J.,Jackson, C.J. (登録日: 2016-11-21, 公開日: 2017-12-06, 最終更新日: 2023-10-04)

主引用文献

Correy, G.J.,Zaidman, D.,Harmelin, A.,Carvalho, S.,Mabbitt, P.D.,Calaora, V.,James, P.J.,Kotze, A.C.,Jackson, C.J.,London, N.
Overcoming insecticide resistance through computational inhibitor design.
Proc.Natl.Acad.Sci.USA, 116:21012-21021, 2019

PubMed Abstract: Insecticides allow control of agricultural pests and disease vectors and are vital for global food security and health. The evolution of resistance to insecticides, such as organophosphates (OPs), is a serious and growing concern. OP resistance often involves sequestration or hydrolysis of OPs by carboxylesterases. Inhibiting carboxylesterases could, therefore, restore the effectiveness of OPs for which resistance has evolved. Here, we use covalent virtual screening to produce nano-/picomolar boronic acid inhibitors of the carboxylesterase αE7 from the agricultural pest as well as a common Gly137Asp αE7 mutant that confers OP resistance. These inhibitors, with high selectivity against human acetylcholinesterase and low to no toxicity in human cells and in mice, act synergistically with the OPs diazinon and malathion to reduce the amount of OP required to kill by up to 16-fold and abolish resistance. The compounds exhibit broad utility in significantly potentiating another OP, chlorpyrifos, against the common pest, the peach-potato aphid (). These compounds represent a solution to OP resistance as well as to environmental concerns regarding overuse of OPs, allowing significant reduction of use without compromising efficacy.

PubMed: 31575743
DOI: 10.1073/pnas.1909130116

実験手法

X-RAY DIFFRACTION (1.75 Å)