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.

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