HUMAN INSULIN DEGRADING ENZYME-INHIBITOR COMPLEX

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH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，可降解几种生理相关底物，如肽激素（胰岛素、胰高血糖素、心房利钠因子和β-内啡肽）、淀粉样肽和肿瘤生长因子-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起着重要作用。因此，IDE是几种人类疾病的有希望的治疗靶点。我们已经解决了底物结合IDE的结构，揭示了这种酶的新的底物识别机制。佛罗里达斯克里普斯的Malcolm Leissring开发了几种高亲和力（2-90 nM）拟肽异羟肟酸盐，可有效抑制IDE活性。我们建议解决IDE抑制剂复合物的结构。该实验的成功不仅为进一步开发IDE抑制剂提供了蓝图，而且还突出了可以作为非拟肽异羟肟酸盐和非异羟肟酸盐IDE抑制剂的对接靶点的口袋。

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.