8S77
Soluble epoxide hydrolase in complex with PROTAC JSF234
This is a non-PDB format compatible entry.
Summary for 8S77
| Entry DOI | 10.2210/pdb8s77/pdb |
| Related | 8S75 8S76 |
| Descriptor | Bifunctional epoxide hydrolase 2, 1,2-ETHANEDIOL, ~{N}-[[4-(cyclopropylsulfonylamino)-2-(trifluoromethyl)phenyl]methyl]-1-ethylsulfonyl-indole-5-carboxamide, ... (5 entities in total) |
| Functional Keywords | complex, structural genomics, structural genomics consortium, sgc, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 85501.87 |
| Authors | Kumar, A.,Schoenfeld, J.,Hiesinger, K.,Lillich, F.,Proschak, E.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2024-02-29, release date: 2025-03-12, Last modification date: 2025-09-24) |
| Primary citation | Schonfeld, J.,Brunst, S.,Ciomirtan, L.,Willmer, L.,Chromik, M.A.,Kumar, A.,Froemel, T.,Liebisch, N.,Hackspacher, A.,Ehrler, J.H.M.,Wintermeier, L.,Hesse, C.,Fiedler, J.,Heering, J.,Freitag, H.,Zardo, P.,Fieguth, H.G.,Bruggerhoff, A.,Jakob, J.,Haupl, B.,Weizel, L.,Kaiser, A.,Schubert-Zsilavecz, M.,Oellerich, T.,Fleming, I.,Schebb, N.H.,Furst, R.,Kannt, A.,Knapp, S.,Proschak, E.,Hiesinger, K. Structure-Based Design of PROTACS for the Degradation of Soluble Epoxide Hydrolase. J.Med.Chem., 68:13728-13749, 2025 Cited by PubMed Abstract: The bifunctional soluble epoxide hydrolase (sEH) represents a promising target for inflammation-related diseases. Although potent inhibitors targeting each domain are available, sEH-PROTACs offer the unique ability to simultaneously block both enzymatic functions, mimicking the sEH knockout phenotype, which has been associated with reducing inflammation, including neuroinflammation, and delaying the progression of Alzheimer's disease. Herein, we report the structure-based development of a potent sEH-PROTAC as a useful pharmacological tool. In order to facilitate a rapid testing of the PROTACs, a cell-based sEH degradation assay was developed utilizing HiBiT technology. We designed and synthesized 24 PROTACs. Furthermore, cocrystallization of sEH with two selected PROTACs allowed us to explore the binding mode and rationalize the most optimal linker length. After comprehensive biological and physicochemical characterization of this series, the most optimal PROTAC was identified in primary human and murine cells, highlighting the potential of using in disease-relevant cell and tissue models. PubMed: 40532036DOI: 10.1021/acs.jmedchem.5c00552 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.36 Å) |
Structure validation
Download full validation report
