7Z28
High-resolution crystal structure of ERAP1 with bound bestatin analogue inhibitor
Summary for 7Z28
| Entry DOI | 10.2210/pdb7z28/pdb |
| Descriptor | Endoplasmic reticulum aminopeptidase 1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total) |
| Functional Keywords | erap1, aminopeptidase, zinc, metallopeptidase, bestatin, bestatin analogue, inhibitor, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 100985.39 |
| Authors | Giastas, P.,Papakyriakou, A.,Stratikos, E.,Vourloumis, D. (deposition date: 2022-02-26, release date: 2022-07-27, Last modification date: 2024-10-23) |
| Primary citation | 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. Discovery of Selective Nanomolar Inhibitors for Insulin-Regulated Aminopeptidase Based on alpha-Hydroxy-beta-amino Acid Derivatives of Bestatin. J.Med.Chem., 65:10098-10117, 2022 Cited by PubMed Abstract: 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 α-hydroxy-β-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 α-hydroxy-β-amino acid derivatives may constitute useful chemical tools and drug leads for this group of aminopeptidases. PubMed: 35833347DOI: 10.1021/acs.jmedchem.2c00904 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.55 Å) |
Structure validation
Download full validation report
