7X5Y

Crystal structure of AtHPPD-Y14240 complex

7X5Y の概要

• エントリーDOI: 10.2210/pdb7x5y/pdb
• 分子名称: 4-hydroxyphenylpyruvate dioxygenase, COBALT (II) ION, (1R,3S)-5-methyl-2-[(1S)-2-naphthalen-1-yloxy-1-oxidanyl-ethyl]cyclohexane-1,3-diol, ... (5 entities in total)
• 機能のキーワード: inhibitor, complex, oxidoreductase
• 由来する生物種: Arabidopsis thaliana (thale cress)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46564.40

構造登録者

Lin, H.-Y.,Dong, J.,Yang, G.-F. (登録日: 2022-03-05, 公開日: 2022-06-01, 最終更新日: 2024-10-23)

主引用文献

Dong, J.,Dong, J.,Yu, X.H.,Yan, Y.C.,Nan, J.X.,Ye, B.Q.,Yang, W.C.,Lin, H.Y.,Yang, G.F.
Discovery of Subnanomolar Inhibitors of 4-Hydroxyphenylpyruvate Dioxygenase via Structure-Based Rational Design.
J.Agric.Food Chem., 71:1170-1177, 2023

PubMed Abstract: High-potency 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors are usually featured by time-dependent inhibition. However, the molecular mechanism underlying time-dependent inhibition by HPPD inhibitors has not been fully elucidated. Here, based on the determination of the HPPD binding mode of natural products, the π-π sandwich stacking interaction was found to be a critical element determining time-dependent inhibition. This result implied that, for the time-dependent inhibitors, strengthening the π-π sandwich stacking interaction might improve their inhibitory efficacy. Consequently, modification with one methyl group on the bicyclic ring of quinazolindione inhibitors was achieved, thereby strengthening the stacking interaction and significantly improving the inhibitory efficacy. Further introduction of bulkier hydrophobic substituents with higher flexibility resulted in a series of HPPD inhibitors with outstanding subnanomolar potency. Exploration of the time-dependent inhibition mechanism and molecular design based on the exploration results are very successful cases of structure-based rational design and provide a guiding reference for future development of HPPD inhibitors.

PubMed: 36599124
DOI: 10.1021/acs.jafc.2c06727

実験手法

X-RAY DIFFRACTION (1.498 Å)