Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22072-7. doi: 10.1073/pnas.1012039107. Epub 2010 Dec 6.
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.
乙酰辅酶 A 羧化酶（ACCs）是至关重要的代谢酶，已成为针对肥胖症、糖尿病和其他疾病的药物开发的靶点。该酶的羧基转移酶（CT）结构域是三种不同类别的除草剂的作用部位，以精吡氟禾草灵、噁唑禾草灵和吡氟酰草胺为代表。我们之前的研究表明，精吡氟禾草灵和噁唑禾草灵结合在酶二聚体界面的 CT 活性部位。然而，这两种化合物探测到二聚体界面的不同区域，仅主要共享与酶相互作用的两个共同锚固点。我们在此报告了酵母 ACC 的 CT 结构域与吡氟酰草胺在 2.8-Å 分辨率下复合物的晶体结构。尽管它们具有化学多样性，但吡氟酰草胺具有与噁唑禾草灵相似的结合模式，并且需要二聚体界面的小构象变化才能结合。与所有三类除草剂结合的 CT 结构域的晶体结构证实了两个锚固点对除草剂结合的重要性。这些结构还为理解除草剂抗性突变和除草剂之间的交叉抗性的分子基础，以及针对植物和人类 ACC 的新抑制剂的设计和开发提供了基础。
