8Y5B

Crystal structure of TRIM21 PRYSPRY (D355A) in complex with (R)-hydroxyl-acepromazine.

これはPDB形式変換不可エントリーです。

8Y5B の概要

• エントリーDOI: 10.2210/pdb8y5b/pdb
• 関連するPDBエントリー: 8Y58 8Y59
• 分子名称: E3 ubiquitin-protein ligase TRIM21, (1~{R})-1-[10-[3-(dimethylamino)propyl]phenothiazin-2-yl]ethanol (3 entities in total)
• 機能のキーワード: trim21, pryspry, (r)-hydroxyl-acepromazine, ligase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 21925.70

構造登録者

Lu, P.,Cheng, Y.,Xue, L.,Ren, X.,Huang, N.,Han, T. (登録日: 2024-01-31, 公開日: 2024-10-09, 最終更新日: 2024-12-25)

主引用文献

Lu, P.,Cheng, Y.,Xue, L.,Ren, X.,Xu, X.,Chen, C.,Cao, L.,Li, J.,Wu, Q.,Sun, S.,Hou, J.,Jia, W.,Wang, W.,Ma, Y.,Jiang, Z.,Li, C.,Qi, X.,Huang, N.,Han, T.
Selective degradation of multimeric proteins by TRIM21-based molecular glue and PROTAC degraders.
Cell, 187:7126-7142.e20, 2024

PubMed Abstract: Targeted protein degradation (TPD) utilizes molecular glues or proteolysis-targeting chimeras (PROTACs) to eliminate disease-causing proteins by promoting their interaction with E3 ubiquitin ligases. Current TPD approaches are limited by reliance on a small number of constitutively active E3 ubiquitin ligases. Here, we report that (S)-ACE-OH, a metabolite of the antipsychotic drug acepromazine, acts as a molecular glue to induce an interaction between the E3 ubiquitin ligase TRIM21 and the nucleoporin NUP98, leading to the degradation of nuclear pore proteins and disruption of nucleocytoplasmic trafficking. Functionalization of acepromazine into PROTACs enabled selective degradation of multimeric proteins, such as those within biomolecular condensates, while sparing monomeric proteins. This selectivity is consistent with the requirement of substrate-induced clustering for TRIM21 activation. As aberrant protein assemblies cause diseases such as autoimmunity, neurodegeneration, and cancer, our findings highlight the potential of TRIM21-based multimer-selective degraders as a strategy to tackle the direct causes of these diseases.

PubMed: 39488207
DOI: 10.1016/j.cell.2024.10.015

実験手法

X-RAY DIFFRACTION (1.74 Å)