8XTV

Crystal structure of AaHPPD-Y14150 complex

これはPDB形式変換不可エントリーです。

8XTV の概要

• エントリーDOI: 10.2210/pdb8xtv/pdb
• 分子名称: 4-hydroxyphenylpyruvate dioxygenase, COBALT (II) ION, [3-ethyl-1-methyl-2,2-bis(oxidanylidene)-2$l^{6},1,3-benzothiadiazol-5-yl]-(1-methyl-5-oxidanyl-pyrazol-4-yl)methanone, ... (4 entities in total)
• 機能のキーワード: complex, inhibitor, oxidoreductase
• 由来する生物種: Aedes aegypti (yellow fever mosquito)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 88020.95

構造登録者

Dong, J.,Lin, H.-Y.,Yang, G.-F. (登録日: 2024-01-11, 公開日: 2025-01-15, 最終更新日: 2025-07-02)

主引用文献

Dong, J.,Fu, Y.X.,Zheng, B.F.,Chen, M.X.,Chen, Q.,Wishwajith, K.,Dong, J.,Lin, H.Y.,Yang, G.F.
Repurposing 4-Hydroxyphenylpyruvate dioxygenase inhibitors as novel agents for mosquito control: A structure-based design approach.
Int.J.Biol.Macromol., 315:144566-144566, 2025

PubMed Abstract: Mosquito-borne diseases remain a significant global health burden, necessitating innovative vector control strategies. 4-Hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors, widely used as herbicides, have been recently explored for their potential to disrupt mosquito tyrosine metabolic pathways, offering a novel approach to mosquito control. This study utilized a structure-based rational design strategy to repurpose existing HPPD inhibitors, such as pyrazole-benzene 2,2-dioxothiadiazole and pyrazole-1,3-isoindolinone hybrids, targeting Aedes aegypti HPPD (AaHPPD). Biochemical assays demonstrated that a series of synthesized hybrid compounds exhibited superior inhibitory activity against mosquito-derived HPPD compared to traditional inhibitors, the IC values of compound a9 and compound c14 are 7.70 nM and 53.80 nM, respectively. Crystallographic analysis showed stable inhibitor binding mediated by chelation with metal ions in the active site and π-π interactions with Phe336 and Phe364. C6/36 cell assays further confirmed elevated tyrosine accumulation and significantly affected energy metabolism in the tricarboxylic acid cycle following treatment with the newly designed inhibitors. These findings highlight the potential of repurposed HPPD inhibitors as safe and effective mosquito control agents with novel mechanisms of action.

PubMed: 40412679
DOI: 10.1016/j.ijbiomac.2025.144566

実験手法

X-RAY DIFFRACTION (1.994 Å)