| Structural highlights
5mj6 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , |
| Activity: | Cystinyl aminopeptidase, with EC number 3.4.11.3 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[LCAP_HUMAN] Release of an N-terminal amino acid, cleaves before cysteine, leucine as well as other amino acids. Degrades peptide hormones such as oxytocin, vasopressin and angiotensin III, and plays a role in maintaining homeostasis during pregnancy. May be involved in the inactivation of neuronal peptides in the brain. Cleaves Met-enkephalin and dynorphin. Binds angiotensin IV and may be the angiotensin IV receptor in the brain.[1] [2] [3]
Publication Abstract from PubMed
Insulin-regulated aminopeptidase (IRAP) is an enzyme with several important biological functions that is known to process a large variety of different peptidic substrates, although the mechanism behind this wide specificity is not clearly understood. We describe a crystal structure of IRAP in complex with a recently developed bioactive and selective inhibitor at 2.53 A resolution. In the presence of this inhibitor, the enzyme adopts a novel conformation in which domains II and IV are juxtaposed, forming a hollow structure that excludes external solvent access to the catalytic center. A loop adjacent to the enzyme's GAMEN motif undergoes structural reconfiguration, allowing the accommodation of bulky inhibitor side chains. Atomic interactions between the inhibitor and IRAP that are unique to this conformation can explain the strong selectivity compared to homologous aminopeptidases ERAP1 and ERAP2. This conformation provides insight on IRAP's catalytic cycle and reveals significant active-site plasticity that may underlie its substrate permissiveness.
Ligand-Induced Conformational Change of Insulin-Regulated Aminopeptidase: Insights on Catalytic Mechanism and Active Site Plasticity.,Mpakali A, Saridakis E, Harlos K, Zhao Y, Kokkala P, Georgiadis D, Giastas P, Papakyriakou A, Stratikos E J Med Chem. 2017 Apr 3. doi: 10.1021/acs.jmedchem.6b01890. PMID:28328206[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Matsumoto H, Nagasaka T, Hattori A, Rogi T, Tsuruoka N, Mizutani S, Tsujimoto M. Expression of placental leucine aminopeptidase/oxytocinase in neuronal cells and its action on neuronal peptides. Eur J Biochem. 2001 Jun;268(11):3259-66. PMID:11389728
- ↑ Albiston AL, McDowall SG, Matsacos D, Sim P, Clune E, Mustafa T, Lee J, Mendelsohn FA, Simpson RJ, Connolly LM, Chai SY. Evidence that the angiotensin IV (AT(4)) receptor is the enzyme insulin-regulated aminopeptidase. J Biol Chem. 2001 Dec 28;276(52):48623-6. Epub 2001 Nov 13. PMID:11707427 doi:http://dx.doi.org/10.1074/jbc.C100512200
- ↑ Tsujimoto M, Mizutani S, Adachi H, Kimura M, Nakazato H, Tomoda Y. Identification of human placental leucine aminopeptidase as oxytocinase. Arch Biochem Biophys. 1992 Feb 1;292(2):388-92. PMID:1731608
- ↑ Mpakali A, Saridakis E, Harlos K, Zhao Y, Kokkala P, Georgiadis D, Giastas P, Papakyriakou A, Stratikos E. Ligand-Induced Conformational Change of Insulin-Regulated Aminopeptidase: Insights on Catalytic Mechanism and Active Site Plasticity. J Med Chem. 2017 Apr 3. doi: 10.1021/acs.jmedchem.6b01890. PMID:28328206 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01890
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