4pj6

Publication Abstract from PubMed

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. This article is protected by copyright. All rights reserved.

Crystal structure of human insulin-regulated aminopeptidase with specificity for cyclic peptides.,Hermans SJ, Ascher DB, Hancock NC, Holien JK, Michell BJ, Chai SY, Morton CJ, Parker MW Protein Sci. 2014 Nov 18. doi: 10.1002/pro.2604. PMID:25408552^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.