A different mechanism for the inhibition of the carboxyltransferase domain of acetyl-coenzyme A carboxylase by tepraloxydim.
Acetyl-CoA carboxylases (ACCs) are crucial metabolic enzymes and are attractive targets for drug discovery. Haloxyfop and tepraloxydim belong to two distinct classes of commercial herbicides and kill sensitive plants by inhibiting the carboxyltransferase (CT) activity of ACC. Our earlier structural studies showed that haloxyfop is bound near the active site of the CT domain, at the interface of its dimer, and a large conformational change in the dimer interface is required for haloxyfop binding. We report here the crystal structure at 2.3 A resolution of the CT domain of yeast ACC in complex with tepraloxydim. The compound has a different mechanism of inhibiting the CT activity compared to haloxyfop, as well as the mammalian ACC inhibitor CP-640186. Tepraloxydim probes a different region of the dimer interface and requires only small but important conformational changes in the enzyme, in contrast to haloxyfop. The binding mode of tepraloxydim explains the structure-activity relationship of these inhibitors, and provides a molecular basis for their distinct sensitivity to some of the resistance mutations, as compared to haloxyfop. Despite the chemical diversity between haloxyfop and tepraloxydim, the compounds do share two binding interactions to the enzyme, which may be important anchoring points for the development of ACC inhibitors.
Xiang
Song
S
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Callaghan
Matthew M
MM
Watson
Keith G
KG
Tong
Liang
L
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D003512:Cyclohexanones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D053209:Herbicide Resistance / Q000235:genetics; D006540:Herbicides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics; D010091:Oximes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology*
D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D006540:Herbicides; D010091:Oximes; C551920:tepraloxydim; D000103:Acetyl-CoA Carboxylase