7zyf

Insulin regulated aminopeptidase (IRAP) in complex with a nanomolar alpha hydroxy beta amino acid based inhibitor.

spinqualitylabelsall models 7zyf, resolution 2.81Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7zyf 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 2.81Å Ligands: BMA, EDO, KFR, MAN, NAG, PEG, TRS, 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 The oxytocinase subfamily of M1 zinc aminopeptidases comprises emerging drug targets, including the ER-resident aminopeptidases 1 and 2 (ERAP1 and ERAP2) and insulin-regulated aminopeptidase (IRAP); however, reports on clinically relevant inhibitors are limited. Here we report a new synthetic approach of high diastereo- and regioselectivity for functionalization of the alpha-hydroxy-beta-amino acid scaffold of bestatin. Stereochemistry and mechanism of inhibition were investigated by a high-resolution X-ray crystal structure of ERAP1 in complex with a micromolar inhibitor. By exploring the P1 side-chain functionalities, we achieve significant potency and selectivity, and we report a cell-active, low-nanomolar inhibitor of IRAP with >120-fold selectivity over homologous enzymes. X-ray crystallographic analysis of IRAP in complex with this inhibitor suggest that interactions with the GAMEN loop is an unappreciated key determinant for potency and selectivity. Overall, our results suggest that alpha-hydroxy-beta-amino acid derivatives may constitute useful chemical tools and drug leads for this group of aminopeptidases. Discovery of Selective Nanomolar Inhibitors for Insulin-Regulated Aminopeptidase Based on alpha-Hydroxy-beta-amino Acid Derivatives of Bestatin.,Vourloumis D, Mavridis I, Athanasoulis A, Temponeras I, Koumantou D, Giastas P, Mpakali A, Magrioti V, Leib J, van Endert P, Stratikos E, Papakyriakou A J Med Chem. 2022 Jul 14. doi: 10.1021/acs.jmedchem.2c00904. PMID:35833347 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aminopeptidase 3D structures

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