The mode of action and the structure of a herbicide in complex with its target: binding of activated hydantocidin to the feedback regulation site of adenylosuccinate synthetase.
(+)-Hydantocidin, a recently discovered natural spironucleoside with potent herbicidal activity, is shown to be a proherbicide that, after phosphorylation at the 5' position, inhibits adenylosuccinate synthetase, an enzyme involved in de novo purine synthesis. The mode of binding of hydantocidin 5'-monophosphate to the target enzyme was analyzed by determining the crystal structure of the enzyme-inhibitor complex at 2.6-A resolution. It was found that adenylosuccinate synthetase binds the phosphorylated compound in the same fashion as it does adenosine 5'-monophosphate, the natural feedback regulator of this enzyme. This work provides the first crystal structure of a herbicide-target complex reported to date.
Fonné-Pfister
R
R
Pharmaceutical Division, Ciba-Geigy Ltd., Basel, Switzerland.
Chemla
P
P
Ward
E
E
Girardet
M
M
Kreuz
K E
KE
Honzatko
R B
RB
Fromm
H J
HJ
Schär
H P
HP
Grütter
M G
MG
Cowan-Jacob
S W
SW
D000265:Adenylosuccinate Synthase / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D018076:DNA, Complementary / Q000032:analysis; D004926:Escherichia coli; D005246:Feedback; D006540:Herbicides / Q000737:chemistry / Q000378:metabolism*; D006827:Hydantoins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D010641:Phenotype; D010944:Plants; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
D018076:DNA, Complementary; D006540:Herbicides; D006827:Hydantoins; C068815:hydantocidin; D000265:Adenylosuccinate Synthase