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

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• 作者：Cheng Yang ; James W. Pflugrath ; Debra L. Camper ; Mendy L. Foster ; Daniel J. Pernich ; and Terence A. Walsh
• 刊名：Biochemistry
• 出版年：2004
• 出版时间：August 17, 2004
• 年：2004
• 卷：43
• 期：32
• 页码：10414 - 10423
• 全文大小：722K
• 年卷期：v.43,no.32(August 17, 2004)
• ISSN：1520-4995

文摘

A high degree of selectivity toward the target site of the pest organism is a desirable attributefor new safer agrochemicals. To assist in the design of novel herbicides, we determined the crystal structuresof the herbicidal target enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD; EC 1.13.11.27) from theplant Arabidopsis thaliana with and without an herbicidal benzoylpyrazole inhibitor that potently inhibitsboth plant and mammalian HPPDs. We also determined the structure of a mammalian (rat) HPPD incomplex 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) selectivitytoward the plant enzyme and was cocrystallized with Arabidopsis HPPD. Detailed comparisons of theplant and mammalian HPPD-ligand structures suggest a structural basis for the high degree of plantselectivity of certain HPPD inhibitors and point to design strategies to obtain potent and selective inhibitorsof plant HPPD as agrochemical leads.