9GJS
ERAP1 in complex with 1-[2-(6-bromo-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)acetamido]-4,4-difluorocyclohexane-1-carboxylic acid
This is a non-PDB format compatible entry.
Summary for 9GJS
| Entry DOI | 10.2210/pdb9gjs/pdb |
| Descriptor | Endoplasmic reticulum aminopeptidase 1, ZINC ION, PHOSPHATE ION, ... (6 entities in total) |
| Functional Keywords | erap1, peptide binding protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 1 |
| Total formula weight | 106893.63 |
| Authors | |
| Primary citation | Hryczanek, R.P.,Hackett, A.S.,Rowland, P.,Chung, C.W.,Convery, M.A.,Holmes, D.S.,Hutchinson, J.P.,Kitchen, S.,Korczynska, J.,Law, R.P.,Lea, J.D.,Liddle, J.,Lonsdale, R.,Neu, M.,Nickels, L.,Phillipou, A.,Rowedder, J.E.,Schneck, J.L.,Scott-Stevens, P.,Sheehan, H.,Tayler, C.L.,Temponeras, I.,Tinworth, C.P.,Walker, A.L.,Wojno-Picon, J.,Young, R.J.,Lindsay, D.M.,Stratikos, E. Optimization of Potent and Selective Cyclohexyl Acid ERAP1 Inhibitors Using Structure- and Property-Based Drug Design. Acs Med.Chem.Lett., 15:2107-2114, 2024 Cited by PubMed Abstract: Endoplasmic reticulum aminopeptidase 1 (ERAP1) cleaves the -terminal amino acids of peptides, which can then bind onto major histocompatibility class I (MHC-I) molecules for presentation onto the cell surface, driving the activation of adaptive immune responses. In cancer, overtrimming of mature antigenic peptides can reduce cytotoxic T-cell responses, and ERAP1 can generate self-antigenic peptides which contribute to autoimmune cellular responses. Therefore, modulation of ERAP1 activity has potential therapeutic indications for cancer immunotherapy and in autoimmune disease. Herein we describe the hit-to-lead optimization of a series of cyclohexyl acid ERAP1 inhibitors, found by X-ray crystallography to bind at an allosteric regulatory site. Structure-based drug design enabled a >1,000-fold increase in ERAP1 enzymatic and cellular activity, resulting in potent and selective tool molecules. For lead compound , rat pharmacokinetic properties showed moderate unbound clearance and oral bioavailability, thus highlighting the promise of the series for further optimization. PubMed: 39691536DOI: 10.1021/acsmedchemlett.4c00401 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.351 Å) |
Structure validation
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