CRYSTAL STRUCTURES OF ACYL-COA CARBOXYLASE AS TARGETS OF CANCER AND OBESITY THER

作为癌症和肥胖靶标的酰基辅酶A羧化酶的晶体结构

• 批准号: 8169928
• 负责人: Shiou-Chuan Tsai
• 金额: $ 0.03万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169928
• 关键词: Acetyl Coenzyme A; Acetyl-CoA Carboxylase; Acyl Coenzyme A; Biotin; Catalytic Domain; Coenzyme A; Commit; Computer Retrieval of Information on Scientific Projects Database; Data; Drug Design; Enzymes; Funding; Future; Grant; Homo; Housing; Institution; Light; Malignant Neoplasms; Metabolic; Methods; Molecular; Mutagenesis; Obesity; Reaction; Regulation; Research; Research Personnel; Resolution; Resources; Solutions; Source; Structure; United States National Institutes of Health; base; carboxylation; diabetes mellitus therapy; fatty acid biosynthesis; indexing; methylmalonyl-coenzyme A; molecular recognition; mutant; success

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Acyl-coenzyme A carboxylases (ACCase), such as acetyl-CoA carboxylase (ACC) or propanyl-CoA carboxylase (PCC), catalyze the carboxylation of acetyl- and propanyl-CoA to provide malonyl- and methylmalonyl-CoA. This carboxylation reaction is one of the most important metabolic regulation checkpoints by committing acetyl-CoA and propanyl?CoA to the biosynthesis of fatty acids. ACC and PCC are therefore a highly promising target for obesity, cancer and diabetes therapy. The core catalytic subunits, pccB and accB, are 360 kDa homo-hexamers, catalyzing the transcarboxylation between biotin-CO2 and acyl-CoA. We solved the apo crystal structures of pccB hexamer to 2.0 ¿. To understand the molecular recognition of ACCase, difffration-quality crystals of both wild type and mutant accB and pccB were grown, diffracted and indexed in-house to 3.5?4 ¿, including apo, binary (enzyme-biotin) and tertiary (enzyme-biotin-acyl CoA) crystals. Some crystal forms will require heavy atom methods (MIR and MAD) for solutions. Beamtime at SSRL will be vital for our success to solve high resolution structures of ACCase. The structures, combined with mutagenesis data, will shed light on the molecular basis of substrate recognition, resulting in the identification of future drug design targets for cancer and obesity therapy.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 酰基辅酶A羧化酶（ACCase），如乙酰辅酶A羧化酶（ACC）或丙酰辅酶A羧化酶（PCC），催化乙酰辅酶A和丙酰辅酶A的羧化以提供丙二酰辅酶A和甲基丙二酰辅酶A。这种羧化反应是最重要的代谢调节检查点之一，通过提交乙酰辅酶A和丙？辅酶A对脂肪酸生物合成的影响。因此，ACC和PCC是肥胖、癌症和糖尿病治疗的非常有前途的靶点。核心催化亚基pccB和accB是360 kDa同源六聚体，催化生物素-CO2和酰基-CoA之间的转羧作用。我们将pccB六聚体的apo晶体结构解析为2.0？。要了解ACC酶的分子识别，衍射质量晶体的野生型和突变体accB和pccB的生长，衍射和索引内部到3.5？包括载脂蛋白、二元（酶-生物素）和三级（酶-生物素-酰基CoA）晶体。某些晶型需要重原子方法（MIR和MAD）来解决。SSRL的Beamtime对于我们成功解决ACCase的高分辨率结构至关重要。结合诱变数据的结构，将揭示底物识别的分子基础，从而确定未来癌症和肥胖治疗的药物设计靶点。