INSULIN DEGRADING ENZYME ALONE AND IN COMPLEX WITH INSULIN

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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 ¿ 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.