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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Molecular basis for the inhibition of the carboxyltransferase domain of acetyl-coenzyme-A carboxylase by haloxyfop and diclofop
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Molecular basis for the inhibition of the carboxyltransferase domain of acetyl-coenzyme-A carboxylase by haloxyfop and diclofop

机译：氟吡咯烷酮和双氯芬普酮抑制乙酰辅酶A羧化酶羧基转移酶结构域的分子基础

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摘要

Acetyl-CoA carboxylases (ACCs) are crucial for the metabolism of fatty acids, making these enzymes important targets for the development of therapeutics against obesity, diabetes, and other diseases. The carboxyltransferase (CT) domain of ACC is the site of action of commercial herbicides, such as haloxyfop, diclofop, and sethoxydim. We have determined the crystal structures at up to 2.5-Angstrom resolution of the CT domain of yeast ACC in complex with the herbicide haloxyfop or diclofop. The inhibitors are bound in the active site, at the interface of the dimer of the CT domain. Unexpectedly, inhibitor binding requires large conformational changes for several residues in this interface, which create a highly conserved hydrophobic pocket that extends deeply into the core of the dimer. Two residues that affect herbicide sensitivity are located in this binding site, and mutation of these residues disrupts the structure of the domain. Other residues in the binding site are strictly conserved among the CT domains.
机译：乙酰辅酶A羧化酶（ACC）对于脂肪酸的代谢至关重要，使这些酶成为开发针对肥胖，糖尿病和其他疾病的疗法的重要目标。 ACC的羧基转移酶（CT）结构域是商品除草剂（如haloxyfop，diclofop和sethoxydim）的作用位点。我们已经确定了与除草剂haloxyfop或diclofop配合使用的酵母ACC CT结构域的分辨率高达2.5埃的晶体结构。抑制剂结合在CT结构域二聚体界面的活性位点。出乎意料的是，抑制剂的结合需要对该界面中的多个残基进行大的构象变化，从而形成高度保守的疏水口袋，该口袋深深地延伸至二聚体的核心。影响除草剂敏感性的两个残基位于该结合位点，这些残基的突变破坏了结构域的结构。结合位点中的其他残基在CT域之间严格保守。

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