title: 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.affiliation: ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Melbourne, Victoria, 3065, Australia.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Hermans
authors.forename: David B
authors.initials: DB
authors.lastname: Ascher
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Hancock
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Holien
authors.forename: Belinda J
authors.initials: BJ
authors.lastname: Michell
authors.forename: Siew Yeen
authors.initials: SY
authors.lastname: Chai
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Morton
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D010122:Cystinyl Aminopeptidase / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000378:metabolism*; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D007328:Insulin; D010456:Peptides, Cyclic; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase
keywords: Alzheimer's disease; aminopeptidase; catalysis; computational modeling; crystallography; cyclic peptide; insulin signaling; memory enhancers