5YY6

Crystal structure of Arabidopsis thaliana HPPD truncated mutant complexed with Benquitrione

5YY6 の概要

• エントリーDOI: 10.2210/pdb5yy6/pdb
• 関連するPDBエントリー: 5CTO
• 分子名称: 4-hydroxyphenylpyruvate dioxygenase, COBALT (II) ION, 3-(2,6-dimethylphenyl)-1-methyl-6-(2-oxidanyl-6-oxidanylidene-cyclohexen-1-yl)carbonyl-quinazoline-2,4-dione, ... (4 entities in total)
• 機能のキーワード: 4-hydroxyphenylpyruvate dioxygenase, type i tyrosinemia, drug discovery, oxidoreductase
• 由来する生物種: Arabidopsis thaliana (Mouse-ear cress)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46295.00

構造登録者

Yang, W.C.,Chen, J.N.,Yang, G.F. (登録日: 2017-12-08, 公開日: 2019-01-16, 最終更新日: 2024-11-13)

主引用文献

Lin, H.Y.,Chen, X.,Chen, J.N.,Wang, D.W.,Wu, F.X.,Lin, S.Y.,Zhan, C.G.,Wu, J.W.,Yang, W.C.,Yang, G.F.
Crystal Structure of 4-Hydroxyphenylpyruvate Dioxygenase in Complex with Substrate Reveals a New Starting Point for Herbicide Discovery.
Research (Wash D C), 2019:2602414-2602414, 2019

PubMed Abstract: 4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a promising target for drug and pesticide discovery. The unknown binding mode of substrate is still a big challenge for the understanding of enzymatic reaction mechanism and novel HPPD inhibitor design. Herein, we determined the first crystal structure of HPPD (HPPD) in complex with its natural substrate (HPPA) at a resolution of 2.80 Å. Then, combination of hybrid quantum mechanics/molecular mechanics (QM/MM) calculations confirmed that HPPA takes keto rather than enol form inside the HPPD active pocket. Subsequent site-directed mutagenesis and kinetic analysis further showed that residues (Phe424, Asn423, Glu394, Gln307, Asn282, and Ser267) played important roles in substrate binding and catalytic cycle. Structural comparison between HPPA-HPPD and holo-HPPD revealed that Gln293 underwent a remarkable rotation upon the HPPA binding and formed H-bond network of Ser267-Asn282-Gln307-Gln293, resulting in the transformation of HPPD from an inactive state to active state. Finally, taking the conformation change of Gln293 as a target, we proposed a new strategy of blocking the transformation of HPPD from inactive state to active state to design a novel inhibitor with value of 24.10 nM towards HPPD. The inhibitor has entered into industry development as the first selective herbicide used for the weed control in sorghum field. The crystal structure of HPPD in complex with the inhibitor (2.40 Å) confirmed the rationality of the design strategy. We believe that the present work provides a new starting point for the understanding of enzymatic reaction mechanism and the design of next generation HPPD inhibitors.

PubMed: 31549053
DOI: 10.34133/2019/2602414

実験手法

X-RAY DIFFRACTION (2.401 Å)