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

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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. Interactive Figure | Interactive Figure | PDB Code(s): 4P8Q; 4PJ6

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Hermans, S. J., Ascher, D. B., Hancock, N. C., Holien, J. K., Michell, B. J., Chai, S. Y., … Parker, M. W. (2015). Crystal structure of human insulin-regulated aminopeptidase with specificity for cyclic peptides. Protein Science, 24(2), 190–199. https://doi.org/10.1002/pro.2604

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