Structural Basis for Herbicidal Inhibitor Selectivity Revealed by Comparison of Crystal Structures of Plant and Mammalian 4-Hydroxyphenylpyruvate Dioxygenases
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) f...
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Published in | Biochemistry (Easton) Vol. 43; no. 32; pp. 10414 - 10423 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Chemical Society
17.08.2004
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Subjects | |
Online Access | Get full text |
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Summary: | 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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Bibliography: | Atomic coordinates of the HPPD complexes have been deposited in the Protein Data Bank (ID codes 1SQD, 1SQI, 1TFZ, 1TG5). istex:327A47DE11AEB5630F816BC8000CE0D8F2989B11 ark:/67375/TPS-DBW30GXN-8 |
ISSN: | 0006-2960 1520-4995 |
DOI: | 10.1021/bi049323o |