6LGT

Complex structure of HPPD with an inhibitor Y16542

Summary for 6LGT

• Entry DOI: 10.2210/pdb6lgt/pdb
• Descriptor: 4-hydroxyphenylpyruvate dioxygenase, COBALT (II) ION, 3-(2-chlorophenyl)-6-(1,3-dimethyl-5-oxidanyl-pyrazol-4-yl)carbonyl-1,5-dimethyl-quinazoline-2,4-dione, ... (5 entities in total)
• Functional Keywords: dioxygenase, inhibitor, complex, oxidoreductase
• Biological source: Arabidopsis thaliana (Mouse-ear cress)
• Total number of polymer chains: 1
• Total formula weight: 49489.80

Authors

Lin, H.Y.,Yang, W.C.,Yang, G.F. (deposition date: 2019-12-05, release date: 2020-10-14, Last modification date: 2024-11-13)

Primary citation

He, B.,Wu, F.X.,Yu, L.K.,Wu, L.,Chen, Q.,Hao, G.F.,Yang, W.C.,Lin, H.Y.,Yang, G.F.
Discovery of Novel Pyrazole-Quinazoline-2,4-dione Hybrids as 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.
J.Agric.Food Chem., 68:5059-5067, 2020

PubMed Abstract: 4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) has been identified as one of the most significant targets in herbicide discovery for resistant weed control. In a continuing effort to discover potent novel HPPD inhibitors, we adopted a ring-expansion strategy to design a series of novel pyrazole-quinazoline-2,4-dione hybrids based on the previously discovered pyrazole-isoindoline-1,3-dione scaffold. One compound, 3-(2-chlorophenyl)-6-(5-hydroxy-1,3-dimethyl-1-pyrazole-4-carbonyl)-1,5-dimethylquinazoline-2,4(1,3)-dione (), displayed excellent potency against HPPD, with an IC value of 84 nM, which is approximately 16-fold more potent than pyrasulfotole (IC = 1359 nM) and 2.7-fold more potent than mesotrione (IC = 226 nM). Furthermore, the co-crystal structure of the HPPD- complex (PDB ID 6LGT) was determined at a resolution of 1.75 Å. Similar to the existing HPPD inhibitors, compound formed a bidentate chelating interaction with the metal ion and a π-π stacking interaction with Phe381 and Phe424. In contrast, -chlorophenyl at the N3 position of quinazoline-2,4-dione with a double conformation was surrounded by hydrophobic residues (Met335, Leu368, Leu427, Phe424, Phe392, and Phe381). Remarkably, the greenhouse assay indicated that most compounds displayed excellent herbicidal activity (complete inhibition) against at least one of the tested weeds at the application rate of 150 g of active ingredient (ai)/ha. Most promisingly, compounds and not only exhibited prominent weed control effects with a broad spectrum but also showed very good crop safety to cotton, peanuts, and corn at the dose of 150 g of ai/ha.

PubMed: 32286826
DOI: 10.1021/acs.jafc.0c00051

Experimental method

X-RAY DIFFRACTION (1.794 Å)