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

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.

• Authors: Stefan J Hermans, David B Ascher, Nancy C Hancock, Jessica K Holien, Belinda J Michell, Siew Yeen Chai, Craig J Morton, Michael W Parker
• Journal: Protein science : a publication of the Protein Society (Protein Sci) Vol. 24 Issue 2 Pg. 190-9 (Feb 2015) ISSN: 1469-896X [Electronic] United States
• PMID: 25408552 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Protein Society.

Chemical References

• Insulin
• Peptides, Cyclic
• Cystinyl Aminopeptidase
• leucyl-cystinyl aminopeptidase

Topics

• Catalytic Domain
• Crystallography, X-Ray
• Cystinyl Aminopeptidase (chemistry, metabolism)
• Humans
• Insulin (metabolism)
• Models, Molecular
• Peptides, Cyclic (metabolism)
• Protein Conformation
• Substrate Specificity