5mj6

Ligand-induced conformational change of Insulin-regulated aminopeptidase: insights on catalytic mechanism and active site plasticity.

spinqualitylabelsall models 5mj6, resolution 2.53Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5mj6 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.53Å Ligands: 7O2, BMA, BR, MAN, NAG, ZN 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aminopeptidase 3D structures

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