INSULIN DEGRADING ENZYME IN COMPLEX WITH NATRIURETIC PEPTIDES

胰岛素降解酶与钠尿肽的复合物

• 批准号: 7956832
• 负责人: WEI-JEN TANG
• 金额: $ 0.47万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956832
• 关键词: Alzheimer' s Disease; Amyloid; Atrial Natriuretic Factor; Bradykinin; Complex; Computer Retrieval of Information on Scientific Projects Database; Development; Funding; Glucagon; Grant; Institution; Insulin; Insulinase; Metabolism; Molecular; Natriuretic Peptides; Non-Insulin-Dependent Diabetes Mellitus; Peptides; Play; Regulation; Research; Research Personnel; Resources; Role; Source; Structure; Transforming Growth Factors; United States National Institutes of Health; Zinc; enzyme mechanism; human disease; novel; peptide hormone; structural biology; therapeutic target

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. The insulin degrading enzyme (IDE) is a 110 kDa zinc metallo-endoprotease that degrades several physiologically relevant substrates such as peptide hormones (insulin, glucagon, atrial natriuretic factor, and beta-endophin), amyloid β peptide, and tumor growth factor-alpha. Functional studies have shown that IDE plays important roles in the regulation of developmental and metabolic processes as well as in the development of type 2 diabetes mellitus and Alzheimer?s disease. Thus, IDE is a promising therapeutic target for several human diseases. We have solved the structures of IDE alone and catalytically inactive IDE in complex with several biologically relevant substrates including insulin, amyloid β, glucagon, and bradykinin. Our structures reveal the novel substrate recognition mechanism of this enzyme. One unique feature of IDE is its ability to distinguish the closely related natriuretic peptides. To understand the molecular mechanism for such substrate selectivity, we propose to solve the structures of IDE in complex with natriuretic peptides.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 胰岛素降解酶 (IDE) 是一种 110 kDa 锌金属内切蛋白酶，可降解多种生理相关底物，如肽激素（胰岛素、胰高血糖素、心房钠尿因子和 β-内啡肽）、淀粉样蛋白 β 肽和肿瘤生长因子 α 。功能研究表明，IDE 在发育和代谢过程的调节以及 2 型糖尿病和阿尔茨海默病的发展中发挥着重要作用。因此，IDE是多种人类疾病的有前景的治疗靶点。我们已经解析了单独的 IDE 以及与几种生物学相关底物（包括胰岛素、β 淀粉样蛋白、胰高血糖素和缓激肽）复合的无催化活性 IDE 的结构。我们的结构揭示了这种酶的新型底物识别机制。 IDE 的一个独特功能是能够区分密切相关的利尿钠肽。为了了解这种底物选择性的分子机制，我们建议解析 IDE 与利钠肽复合物的结构。