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

Autor:	Nancy C. Hancock, Siew Yeen Chai, Michael W. Parker, Jessica K. Holien, S.J. Hermans, David B. Ascher, Craig J. Morton, Belinda J. Michell
Rok vydání:	2014
Předmět:	chemistry.chemical_classification biology Cystinyl Aminopeptidase Exopeptidase Biochemistry Aminopeptidase Cyclic peptide Protein structure chemistry Docking (molecular) Hydrolase biology.protein Enhancer Molecular Biology
Zdroj:	Protein Science. 24:190-199
ISSN:	0961-8368
Popis:	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.
Databáze:	OpenAIRE
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