Crystal structure of human insulin-regulated aminopeptidase with specificity for cyclic peptides

Stefan J Hermans, David B Ascher, Nancy C Hancock, Jessica K Holien, Belinda J Michell, Siew Yeen Yeen Chai, Craig J Morton, Michael W Parker

Research output: Contribution to journalArticleResearchpeer-review

33 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)190 - 199
Number of pages10
JournalProtein Science
Volume24
Issue number2
DOIs
Publication statusPublished - 2015

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