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

24 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

Cite this

Hermans, S. J., Ascher, D. B., Hancock, N. C., Holien, J. K., Michell, B. J., Chai, S. Y. 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
Hermans, Stefan J ; Ascher, David B ; Hancock, Nancy C ; Holien, Jessica K ; Michell, Belinda J ; Chai, Siew Yeen Yeen ; Morton, Craig J ; Parker, Michael W. / Crystal structure of human insulin-regulated aminopeptidase with specificity for cyclic peptides. In: Protein Science. 2015 ; Vol. 24, No. 2. pp. 190 - 199.
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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.",
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Hermans, SJ, Ascher, DB, Hancock, NC, Holien, JK, Michell, BJ, Chai, SYY, Morton, CJ & Parker, MW 2015, 'Crystal structure of human insulin-regulated aminopeptidase with specificity for cyclic peptides', Protein Science, vol. 24, no. 2, pp. 190 - 199. https://doi.org/10.1002/pro.2604

Crystal structure of human insulin-regulated aminopeptidase with specificity for cyclic peptides. / Hermans, Stefan J; Ascher, David B; Hancock, Nancy C; Holien, Jessica K; Michell, Belinda J; Chai, Siew Yeen Yeen; Morton, Craig J; Parker, Michael W.

In: Protein Science, Vol. 24, No. 2, 2015, p. 190 - 199.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Hermans, Stefan J

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AU - Michell, Belinda J

AU - Chai, Siew Yeen Yeen

AU - Morton, Craig J

AU - Parker, Michael W

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