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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 酰基辅酶A羧酸酶（ACCASE），例如乙酰-COA羧化酶（ACC）或丙基-COA羧化酶（PCC），催化乙酰基 - 丙基和丙酰辅酶A的羧化，以提供丙酰酰基 - 和甲基氨基甲基甲酰基-COA。这种羧化反应是最重要的代谢调节检查点之一，它通过将乙酰辅酶A和丙基coA定为脂肪酸的生物合成。因此，ACC和PCC是核心催化亚基PCCB和ACCB的高度希望，是360 kDa同型己糖，催化了生物素-CO2和酰基-COA之间的转羧化。我们将PCCB六聚体的APO晶体结构求解为2.0。为了了解ACACASE的分子识别，野生型和突变体ACCB和PCCB的差异 - 质量晶体被种植，衍射并在内部索引至3.5？4€，包括Apo，二进制（酶 - 生物素）和第三级（酶 - 二酰胺 - 生物素-Acyl COA）晶体。某些晶体形式将需要重大原子方法（MIR和MAD）才能解决方案。 SSRL的Beamtime对于我们的成功解决高分辨率结构至关重要。结构与诱变数据相结合，将阐明底物识别的分子基础，从而鉴定出未来的癌症和肥胖症药物设计目标。