Structural Basis for Herbicidal Inhibitor Selectivity Revealed by Comparison of Crystal Structures of Plant and Mammalian 4-Hydroxyphenylpyruvate Dioxygenases

• Published in: Biochemistry (Easton) Vol. 43; no. 32; pp. 10414 - 10423
• Main Authors: Yang, Cheng, Pflugrath, James W, Camper, Debra L, Foster, Mendy L, Pernich, Daniel J, Walsh, Terence A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 17.08.2004
• Subjects: 4-Hydroxyphenylpyruvate Dioxygenase - chemistry; 4-Hydroxyphenylpyruvate Dioxygenase - metabolism; Amino Acid Sequence; Animals; Arabidopsis - chemistry; Arabidopsis - enzymology; Arabidopsis - genetics; Binding Sites; Crystallography, X-Ray; Enzyme Inhibitors - pharmacology; Herbicides - pharmacology; Models, Molecular; Molecular Sequence Data; Molecular Structure; Protein Conformation; Pyrazoles - pharmacology; Rats; Sequence Homology, Amino Acid; Structure-Activity Relationship
• DOI: 10.1021/bi049323o
• ISSN: 0006-2960

A high degree of selectivity toward the target site of the pest organism is a desirable attribute for new safer agrochemicals. To assist in the design of novel herbicides, we determined the crystal structures of the herbicidal target enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD; EC 1.13.11.27) from the plant Arabidopsis thaliana with and without an herbicidal benzoylpyrazole inhibitor that potently inhibits both plant and mammalian HPPDs. We also determined the structure of a mammalian (rat) HPPD in complex with the same nonselective inhibitor. From a screening campaign of over 1000 HPPD inhibitors, six highly plant-selective inhibitors were found. One of these had remarkable (>1600-fold) selectivity toward the plant enzyme and was cocrystallized with Arabidopsis HPPD. Detailed comparisons of the plant and mammalian HPPD−ligand structures suggest a structural basis for the high degree of plant selectivity of certain HPPD inhibitors and point to design strategies to obtain potent and selective inhibitors of plant HPPD as agrochemical leads.