Mechanism for the inhibition of the carboxyltransferase domain of acetyl-coenzyme A carboxylase by pinoxaden.
Acetyl-CoA carboxylases (ACCs) are crucial metabolic enzymes and have been targeted for drug development against obesity, diabetes, and other diseases. The carboxyltransferase (CT) domain of this enzyme is the site of action for three different classes of herbicides, as represented by haloxyfop, tepraloxydim, and pinoxaden. Our earlier studies have demonstrated that haloxyfop and tepraloxydim bind in the CT active site at the interface of its dimer. However, the two compounds probe distinct regions of the dimer interface, sharing primarily only two common anchoring points of interaction with the enzyme. We report here the crystal structure of the CT domain of yeast ACC in complex with pinoxaden at 2.8-Å resolution. Despite their chemical diversity, pinoxaden has a similar binding mode as tepraloxydim and requires a small conformational change in the dimer interface for binding. Crystal structures of the CT domain in complex with all three classes of herbicides confirm the importance of the two anchoring points for herbicide binding. The structures also provide a foundation for understanding the molecular basis of the herbicide resistance mutations and cross resistance among the herbicides, as well as for the design and development of new inhibitors against plant and human ACCs.
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Linda P C
LP
Yu
Yi Seul
YS
Kim
Liang
L
Tong
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000737:chemistry; D019878:Carboxyl and Carbamoyl Transferases; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006540:Herbicides / Q000737:chemistry; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry*; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D006540:Herbicides; D006574:Heterocyclic Compounds, 2-Ring; D029701:Saccharomyces cerevisiae Proteins; D019878:Carboxyl and Carbamoyl Transferases; D000103:Acetyl-CoA Carboxylase; C542519:pinoxaden