8R5D

Crystal structure of human TRIM7 PRYSPRY domain

8R5D の概要

• エントリーDOI: 10.2210/pdb8r5d/pdb
• 分子名称: E3 ubiquitin-protein ligase TRIM7, MALONIC ACID, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: trim7, e3-ligase, structural genomics, structural genomics consortium, sgc, ligase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 40673.83

構造登録者

Munoz Sosa, C.J.,Kraemer, A.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2023-11-16, 公開日: 2024-01-17, 最終更新日: 2024-07-31)

主引用文献

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

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: 38934237
DOI: 10.1021/acschembio.4c00301

実験手法

X-RAY DIFFRACTION (1.8 Å)