9I0T
Crystal structure of TRIM25 PRYSPRY covalently bound to 2-chloro-1-[4-(3-methyl-4-phenyl-phenyl)carbonyl-1,4-diazepan-1-yl]ethanone
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Summary for 9I0T
| Entry DOI | 10.2210/pdb9i0t/pdb |
| Descriptor | E3 ubiquitin/ISG15 ligase TRIM25, 1-[4-(3-methyl-4-phenyl-phenyl)carbonyl-1,4-diazepan-1-yl]ethanone (3 entities in total) |
| Functional Keywords | ubiquitin, e3 ligase, small molecule ligand, pryspry, ligase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 23031.62 |
| Authors | McPhie, K.A.,Esposito, D.,Rittinger, K. (deposition date: 2025-01-15, release date: 2025-05-21, Last modification date: 2025-06-25) |
| Primary citation | McPhie, K.A.,Esposito, D.,Pettinger, J.,Norman, D.,Werner, T.,Mathieson, T.,Bush, J.T.,Rittinger, K. Discovery and optimisation of a covalent ligand for TRIM25 and its application to targeted protein ubiquitination. Chem Sci, 16:10432-10443, 2025 Cited by PubMed Abstract: The tripartite motif (TRIM) family of RING-type E3 ligases catalyses the formation of many different types of ubiquitin chains, and as such, plays important roles in diverse cellular functions, ranging from immune regulation to cancer signalling pathways. Few ligands have been discovered for TRIM E3 ligases, and these E3s are under-represented in the rapidly expanding field of induced proximity. Here we present the identification of a novel covalent ligand for the PRYSPRY substrate binding domain of TRIM25. We employ covalent fragment screening coupled with high-throughput chemistry direct-to-biology optimisation to efficiently elaborate covalent fragment hits. We demonstrate that our optimised ligand enhances the auto-ubiquitination activity of TRIM25 and engages TRIM25 in live cells. We also present the X-ray crystal structure of TRIM25 PRYSPRY in complex with this covalent ligand. Finally, we incorporate our optimised ligand into heterobifunctional proximity-inducing compounds and demonstrate the targeted ubiquitination of a neosubstrate by TRIM25. PubMed: 40365055DOI: 10.1039/d5sc01540e PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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