INSULIN DEGRADING ENZYME IN COMPLEX WITH NATRIURETIC PEPTIDES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 胰岛素降解酶(IDE)是一种110 kDa的锌金属内切酶，可降解多种生理相关底物，如多肽激素(胰岛素、胰升糖素、心房利钠因子和β-内啡肽)、淀粉样多肽和肿瘤生长因子-α。功能研究表明，IDE在发育和代谢过程的调节以及在2型糖尿病和阿尔茨海默病的发生发展中发挥重要作用。因此，IDE是几种人类疾病的很有前途的治疗靶点。我们已经解决了IDE单独的结构和与几种生物相关底物包括胰岛素、淀粉样蛋白、胰高血糖素和缓激肽的复合体中催化失活的IDE。我们的结构揭示了这种酶的新的底物识别机制。IDE的一个独特特征是它能够区分密切相关的利钠肽。为了了解底物选择性的分子机制，我们建议解决与利钠肽形成的络合物中的IDE的结构。

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.