INSULIN DEGRADING ENZYME IN COMPLEX WITH THE NOVEL SUBSTRATES

胰岛素降解酶与新型底物的复合物

• 批准号: 7956828
• 负责人: WEI-JEN TANG
• 金额: $ 2.36万
• 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/7956828
• 关键词: Alzheimer' s Disease; Amyloid; Atrial Natriuretic Factor; Bradykinin; Charge; Complex; Computer Retrieval of Information on Scientific Projects Database; Development; Funding; Glucagon; Grant; Institution; Insulin; Insulin-Like Growth Factor II; Insulinase; Knowledge; Metabolism; 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 substrate; 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 many physiologically relevant substrates such as peptide hormones (insulin, insulin-like growth factor-II, 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 how size, charge distribution, and the propensity of unfolding of IDE substrates could contribute their selective cleavages by IDE. We hypothesize that the list of IDE substrates is incomplete and our knowledge in the interaction of IDE with IDE substrates can be used to identify the novel substrates. Using this strategy, we have identified several novel IDE substrates and would propose to solve the structures of IDE with these substrates.

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。子项目和 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，可降解许多生理相关底物，如肽激素（胰岛素、胰岛素样生长因子-II、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 IDE 底物的尺寸、电荷分布和展开倾向如何影响 IDE 的选择性裂解。我们假设 IDE 底物列表不完整，我们在 IDE 与 IDE 底物相互作用方面的知识可用于识别新型底物。使用这种策略，我们已经确定了几种新颖的 IDE 基板，并建议用这些基板来解决 IDE 的结构。