1. Crystal structure of human insulin-regulated aminopeptidase with specificity for cyclic peptides.
- Author
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Hermans, Stefan J., Ascher, David B., Hancock, Nancy C., Holien, Jessica K., Michell, Belinda J., Chai, Siew Yeen, Morton, Craig J., and Parker, Michael W.
- Abstract
Insulin-regulated aminopeptidase (IRAP or oxytocinase) is a membrane-bound zinc-metallopeptidase that cleaves neuroactive peptides in the brain and produces memory enhancing effects when inhibited. We have determined the crystal structure of human IRAP revealing a closed, four domain arrangement with a large, mostly buried cavity abutting the active site. The structure reveals that the GAMEN exopeptidase loop adopts a very different conformation from other aminopeptidases, thus explaining IRAP's unique specificity for cyclic peptides such as oxytocin and vasopressin. Computational docking of a series of IRAP-specific cognitive enhancers into the crystal structure provides a molecular basis for their structure-activity relationships and demonstrates that the structure will be a powerful tool in the development of new classes of cognitive enhancers for treating a variety of memory disorders such as Alzheimer's disease. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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