8PD6
Crystal structure of the TRIM58 PRY-SPRY domain in complex with TRIM-473
Summary for 8PD6
| Entry DOI | 10.2210/pdb8pd6/pdb |
| Related | 8PD4 |
| Descriptor | E3 ubiquitin-protein ligase TRIM58, ~{N}2-[3-(dimethylamino)propyl]-6-phenyl-~{N}4-(piperidin-4-ylmethyl)quinazoline-2,4-diamine, MAGNESIUM ION, ... (6 entities in total) |
| Functional Keywords | e3 ligase, trim58, pry-spry, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 24799.28 |
| Authors | Renatus, M.,Hoegenauer, K.,Schroeder, M. (deposition date: 2023-06-11, release date: 2024-01-31, Last modification date: 2024-02-07) |
| Primary citation | Hoegenauer, K.,An, S.,Axford, J.,Benander, C.,Bergsdorf, C.,Botsch, J.,Chau, S.,Fernandez, C.,Gleim, S.,Hassiepen, U.,Hunziker, J.,Joly, E.,Keller, A.,Lopez Romero, S.,Maher, R.,Mangold, A.S.,Mickanin, C.,Mihalic, M.,Neuner, P.,Patterson, A.W.,Perruccio, F.,Roggo, S.,Scesa, J.,Schroder, M.,Shkoza, D.,Thai, B.,Vulpetti, A.,Renatus, M.,Reece-Hoyes, J.S. Discovery of Ligands for TRIM58, a Novel Tissue-Selective E3 Ligase. Acs Med.Chem.Lett., 14:1631-1639, 2023 Cited by PubMed Abstract: Redirecting E3 ligases to neo-substrates, leading to their proteasomal disassembly, known as targeted protein degradation (TPD), has emerged as a promising alternative to traditional, occupancy-driven pharmacology. Although the field has expanded tremendously over the past years, the choice of E3 ligases remains limited, with an almost exclusive focus on CRBN and VHL. Here, we report the discovery of novel ligands to the PRY-SPRY domain of TRIM58, a RING ligase that is specifically expressed in erythroid precursor cells. A DSF screen, followed by validation using additional biophysical methods, led to the identification of TRIM58 ligand . A basic SAR around the chemotype was established by utilizing a competitive binding assay employing a short FP peptide probe derived from an endogenous TRIM58 substrate. The X-ray co-crystal structure of TRIM58 in complex with gave insights into the binding mode and potential exit vectors for bifunctional degrader design. PubMed: 38116426DOI: 10.1021/acsmedchemlett.3c00259 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.3 Å) |
Structure validation
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