20-21 November 2014
National Centre for Synchrotron Science
Australia/Melbourne timezone
Save the date: User Meeting 2015 - 26-27 November

Crystal Structure of Human Insulin-Regulated Aminopeptidase

21 Nov 2014, 12:25
Oliphant Auditorium ()

Oliphant Auditorium

Oral Structural Biology Structural Biology II


Dr Stefan Hermans (St Vincent's Institute)


Dementia is the single greatest cause of disability in older Australians afflicting almost one in ten over the age of 65. In the absence of curative therapies, current treatments aimed at enhancing working memory target the cholinergic system and demonstrate limited efficacy, underpinning the need for a new class of cognitive enhancing drug. Insulin-regulated aminopeptidase (IRAP) is a membrane-bound zinc-metallopeptidase that cleaves neuroactive peptides in the brain and its inhibition gives rise to memory enhancing effects in both normal and memory-impaired rodents . Using a large scale insect cell expression system to produce milligram quantities of protein suitable for crystallography, and the Micro Crystallography Beamline at the Australian Synchrotron, we have determined the crystal structure of human IRAP to 2.96 Å. This structure revealed a semi-closed, four domain arrangement with a large, mostly buried cavity adjacent to the active site as well as a dimer interface located in the C-terminal domain. A comparison of the catalytic domain with related aminopeptidases revealed a strikingly different conformation of the GAMEN exopeptidase loop that explains IRAP’s unique specificity for cyclic peptides such as oxytocin and vasopressin. This structure will be a powerful tool in the development of new classes of cognitive enhancers for treating memory disorders such as Alzheimer's dementia.
Keywords or phrases (comma separated) Alzheimer's disease, Memory enhancing, Crystallography, Aminopeptidase

Primary author

Dr Stefan Hermans (St Vincent's Institute)


Dr Belinda Michell (St Vincent's Institute) Dr Craig Morton (St Vincent's Institute for Medical Research) Dr David Ascher (St Vincent's Institute) Dr Jessica Holien (St Vincent's Institute) Prof. Michael Parker (St Vincent's Institute) Ms Nancy Hancock (St Vincent's Institute) Dr Siew Yeen Chai (Monash University)

Presentation Materials

Your browser is out of date!

Update your browser to view this website correctly. Update my browser now