6j63

Crystal structure of Arabidopsis thaliana HPPD complexed with NTBC

spinqualitylabelsall models 6j63, resolution 2.62Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6j63 is a 4 chain structure with sequence from Arath. This structure supersedes the now removed PDB entry 5cto. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: FE, NTD Gene: HPD (ARATH) Activity: 4-hydroxyphenylpyruvate dioxygenase, with EC number 1.13.11.27 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Slow-binding inhibitors with long residence time on the target often display superior efficacy in vivo. Rationally designing inhibitors with low off-target rates is restricted by a limited understanding of the structural basis of slow-binding inhibition kinetics in enzyme-drug interactions. 4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for drug and herbicide development. Although the time-dependent behavior of HPPD inhibitors has been studied for decades, its structural basis and mechanism remain unclear. Herein, we report a detailed experimental and computational study that explores structures for illustrating the slow-binding inhibition kinetics of HPPD. We observed the conformational change of Phe428 at the C-terminal alpha-helix in the inhibitor-bound structures and further identified that the inhibition kinetics of drugs are related to steric hindrance of Phe428. These detailed structural and mechanistic insights illustrate that steric hindrance is highly associated with the time-dependent behavior of HPPD inhibitors. These findings may enable rational design of new potent HPPD-targeted drugs or herbicides with longer target residence time and improved properties. DATABASE: Structure data are available in the PDB under the accession numbers 5CTO (released), 5DHW (released), and 5YWG (released). Molecular insights into the mechanism of 4-hydroxyphenylpyruvate dioxygenase inhibition: enzyme kinetics, X-ray crystallography and computational simulations.,Lin HY, Yang JF, Wang DW, Hao GF, Dong JQ, Wang YX, Yang WC, Wu JW, Zhan CG, Yang GF FEBS J. 2019 Mar;286(5):975-990. doi: 10.1111/febs.14747. Epub 2019 Jan 25. PMID:30632699 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dioxygenase 3D structures

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