8R5C
Crystal structure of human TRIM7 PRYSPRY domain bound to (2-(1-oxoisoindolin-2-yl)-3-phenylpropanoyl)-L-glutamine
Summary for 8R5C
| Entry DOI | 10.2210/pdb8r5c/pdb |
| Descriptor | E3 ubiquitin-protein ligase TRIM7, (2~{S})-5-azanyl-5-oxidanylidene-2-[[(2~{S})-2-(3-oxidanylidene-1~{H}-isoindol-2-yl)-3-phenyl-propanoyl]amino]pentanoic acid, 1,2-ETHANEDIOL, ... (5 entities in total) |
| Functional Keywords | trim7, e3-ligase, ligand, ligase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 20642.16 |
| Authors | Munoz Sosa, C.J.,Kraemer, A.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2023-11-16, release date: 2024-01-17, Last modification date: 2024-07-31) |
| Primary citation | Munoz Sosa, C.J.,Lenz, C.,Hamann, A.,Farges, F.,Dopfer, J.,Kramer, A.,Cherkashyna, V.,Tarnovskiy, A.,Moroz, Y.S.,Proschak, E.,Nemec, V.,Muller, S.,Saxena, K.,Knapp, S. A C-Degron Structure-Based Approach for the Development of Ligands Targeting the E3 Ligase TRIM7. Acs Chem.Biol., 19:1638-1647, 2024 Cited by PubMed Abstract: TRIM7 is a ubiquitin E3 ligase with key regulatory functions, mediating viral infection, tumor biology, innate immunity, and cellular processes, such as autophagy and ferroptosis. It contains a PRYSPRY domain that specifically recognizes degron sequences containing C-terminal glutamine. Ligands that bind to the TRIM7 PRYSPRY domain may have applications in the treatment of viral infections, as modulators of inflammation, and in the design of a new class of PROTACs (PROteolysis TArgeting Chimeras) that mediate the selective degradation of therapeutically relevant proteins (POIs). Here, we developed an assay toolbox for the comprehensive evaluation of TRIM7 ligands. Using TRIM7 degron sequences together with a structure-based design, we developed the first series of peptidomimetic ligands with low micromolar affinity. The terminal carboxylate moiety was required for ligand activity but prevented cell penetration. A prodrug strategy using an ethyl ester resulted in enhanced permeability, which was evaluated using confocal imaging. PubMed: 38934237DOI: 10.1021/acschembio.4c00301 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
Download full validation report
