4PJ6

Crystal Structure of Human Insulin Regulated Aminopeptidase with Lysine in Active Site

Summary for 4PJ6

• Entry DOI: 10.2210/pdb4pj6/pdb
• Descriptor: Leucyl-cystinyl aminopeptidase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ZINC ION, ... (6 entities in total)
• Functional Keywords: aminopeptidase, metalloprotease, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 204621.70

Authors

Hermans, S.J.,Ascher, D.B.,Hancock, N.C.,Holien, J.K.,Michell, B.,Morton, C.J.,Parker, M.W. (deposition date: 2014-05-12, release date: 2014-12-03, Last modification date: 2024-10-30)

Primary citation

Hermans, S.J.,Ascher, D.B.,Hancock, N.C.,Holien, J.K.,Michell, B.J.,Yeen Chai, S.,Morton, C.J.,Parker, M.W.
Crystal structure of human insulin-regulated aminopeptidase with specificity for cyclic peptides.
Protein Sci., 24:190-199, 2015

PubMed 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.

PubMed: 25408552
DOI: 10.1002/pro.2604

Experimental method

X-RAY DIFFRACTION (2.96 Å)