HUMAN INSULIN DEGRADING ENZYME-INHIBITOR COMPLEX

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2型糖尿病和阿尔茨海默病的发生发展中发挥着重要作用。因此，IDE是几种人类疾病的很有前途的治疗靶点。我们已经解决了底物结合IDE的结构，以揭示该酶新的底物识别机制。佛罗里达州斯克里普斯公司的马尔科姆·莱斯林已经开发出几种高亲和力(2-90 NM)的仿肽羟胺酸盐，可以有效地抑制IDE活性。我们提出要解决IDE-抑制剂络合物的结构问题。这项实验的成功不仅将为进一步开发IDE抑制剂提供蓝图，而且还将突出可能作为非肽类异羟甲酸酯和非异羟甲酸酯IDE抑制剂对接目标的口袋。

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 substrate bound IDE to reveal the novel substrate recognition mechanism of this enzyme. Malcolm Leissring at Florida Scripps has developed several high affinity (2-90 nM) peptidomimetic hydroxamates that can potently inhibit the IDE activity. We propose to solve the structures of IDE-inhibitor complexes. Success in this experiment will not only provide the blueprint to further develop IDE inhibitors but also highlight the pockets that could serve as the docking target for non-peptidomimetic hydroxamate and non-hydroxamate IDE inhibitors.