6t6r

Human endoplasmic reticulum aminopeptidase 1 (ERAP1) in complex with (4aR,5S,6R,8S,8aR)-5-(2-(Furan-3-yl)ethyl)-8-hydroxy-5,6,8a-trimethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylic acidHuman endoplasmic reticulum aminopeptidase 1 (ERAP1) in complex with (4aR,5S,6R,8S,8aR)-5-(2-(Furan-3-yl)ethyl)-8-hydroxy-5,6,8a-trimethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid

Structural highlights 6t6r is a 1 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 1.67Å Ligands: , , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ERAP1_HUMAN Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Strongly prefers substrates 9-16 residues long. Rapidly degrades 13-mer to a 9-mer and then stops. Preferentially hydrolyzes the residue Leu and peptides with a hydrophobic C-terminus, while it has weak activity toward peptides with charged C-terminus. May play a role in the inactivation of peptide hormones. May be involved in the regulation of blood pressure through the inactivation of angiotensin II and/or the generation of bradykinin in the kidney. Publication Abstract from PubMed ER aminopeptidase 1 (ERAP1) is an intracellular enzyme that generates antigenic peptides and is an emerging target for cancer immunotherapy and the control of autoimmunity. ERAP1 inhibitors described previously target the active site and are limited in selectivity, minimizing their clinical potential. To address this, we targeted the regulatory site of ERAP1 using a high-throughput screen and discovered a small molecule hit that is highly selective for ERAP1. (4aR,5S,6R,8S,8aR)-5-(2-(Furan-3-yl)ethyl)-8-hydroxy-5,6,8a-trimethyl-3,4,4a,5,6, 7,8,8a-octahydronaphthalene-1-carboxylic acid is a natural product found in Dodonaea viscosa that constitutes a submicromolar, highly selective, and cell-active modulator of ERAP1. Although the compound activates hydrolysis of small model substrates, it is a competitive inhibitor for physiologically relevant longer peptides. Crystallographic analysis confirmed that the compound targets the regulatory site of the enzyme that normally binds the C-terminus of the peptide substrate. Our findings constitute a novel starting point for the development of selective ERAP1 modulators that have potential for further clinical development. Targeting the Regulatory Site of ER Aminopeptidase 1 Leads to the Discovery of a Natural Product Modulator of Antigen Presentation.,Liddle J, Hutchinson JP, Kitchen S, Rowland P, Neu M, Cecconie T, Holmes DS, Jones E, Korczynska J, Koumantou D, Lea JD, Nickels L, Pemberton M, Phillipou A, Schneck JL, Sheehan H, Tinworth CP, Uings I, Wojno-Picon J, Young RJ, Stratikos E J Med Chem. 2020 Mar 9. doi: 10.1021/acs.jmedchem.9b02123. PMID:32109056 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aminopeptidase 3D structures

spinqualitylabelsall models 6t6r, resolution 1.67Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image