Download MendeleyStructural basis for herbicidal inhibitor selectivity revealed by comparison of crystal structures of plant and Mammalian 4-hydroxyphenylpyruvate dioxygenases
Yang, C., Pflugrath, J.W., Camper, D.L., Foster, M.L., Pernich, D.J., Walsh, T.A.(2004) Biochemistry 43: 10414-10423
- PubMed: 15301540
- DOI: https://doi.org/10.1021/bi049323o
- Primary Citation of Related Structures:
1SQD, 1SQI, 1TFZ, 1TG5 - PubMed Abstract:
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.
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