INSULIN DEGRADING ENZYME IN COMPLEX WITH THE NOVEL SUBSTRATES

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，能降解许多生理相关底物，如多肽激素(胰岛素、胰岛素样生长因子-II、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IDE底物的大小、电荷分布和展开倾向如何有助于其被IDE选择性切割。我们假设IDE底物的列表是不完整的，我们在IDE与IDE底物相互作用方面的知识可以用来识别新的底物。利用这一策略，我们已经确定了几种新型的IDE衬底，并将提出用这些衬底来解决IDE的结构问题。

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.