The Structure of IRAP: Breaking the Cycle — ASN Events
  1. Schedule
  2. Session Eight - Processing and Turnover
  3. The Structure of IRAP: Breaking the Cycle

The Structure of IRAP: Breaking the Cycle (#17)

Craig J Morton 1 , Stefan J Hermans 1 , David B Ascher 1 , Nancy C Hancock 1 , Jessica K Holien 1 , Belinda J Michell 1 , Siew Yeen Chai 2 , Michael W Parker 1 3
  1. ACRF Rational Drug Discovery Centre, St Vincent's Institute, Melbourne, Australia
  2. Department of Physiology, Monash University, Clayton, VIC, Australia
  3. Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Parkville, VIC, Australia
Insulin-regulated aminopeptidase (IRAP, oxytocinase) is a membrane-bound zinc- metallopeptidase with roles in a variety of important physiological processes including pregnancy, memory, glucose homeostasis and antigen processing and possessing a unique role in processing cyclic peptides that contain an N-terminal disulfide, such as oxytocin and vasopressin. Of particular interest is the observation that inhibition of IRAP’s aminopeptidase activity in the brain in rodents improves cognitive performance across a range of tasks (1, 2). 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 details of the active site that explain IRAP’s unique specificity for cyclic peptides and provides insight into the development of improved IRAP-specific inhibitors.
  1. Albiston AL, Morton CJ, Ng HL, Pham V, Yeatman HR, Ye S, Fernando RN, De Bundel D, Ascher DB, Mendelsohn FA, Parker MW, Chai SY. 2008. Identification and characterization of a new cognitive enhancer based on inhibition of insulin-regulated aminopeptidase. Faseb J 22:4209-4217.
  2. Albiston AL, Diwakarla S, Fernando RN, Mountford SJ, Yeatman HR, Morgan B, Pham V, Holien JK, Parker MW, Thompson PE, Chai SY. 2011. Identification and development of specific inhibitors for insulin-regulated aminopeptidase as a new class of cognitive enhancers. British journal of pharmacology 164:37-47.