4P8Q: Crystal Structure Of Human Insulin Regulated Aminopeptidase With Alanine In Active Site

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.
PDB ID: 4P8QDownload
MMDB ID: 125208
PDB Deposition Date: 2014/3/31
Updated in MMDB: 2014/12
Experimental Method:
x-ray diffraction
Resolution: 3.02  Å
Source Organism:
Similar Structures:
Biological Unit for 4P8Q: dimeric; determined by author and by software (PISA)
Molecular Components in 4P8Q
Label Count Molecule
Proteins (2 molecules)
Leucyl-cystinyl Aminopeptidase(Gene symbol: LNPEP)
Molecule annotation
Chemicals (25 molecules)
* Click molecule labels to explore molecular sequence information.

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