7LPS

Crystal structure of DDB1-CRBN-ALV1 complex bound to Helios (IKZF2 ZF2)

7LPS の概要

• エントリーDOI: 10.2210/pdb7lps/pdb
• 分子名称: DNA damage-binding protein 1, Protein cereblon, Zinc finger protein Helios, ... (5 entities in total)
• 機能のキーワード: crbn, ddb1, ikzf2, alv, degradation, e3 ligase, ligase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 703337.26

構造登録者

Nowak, R.P.,Fischer, E.S. (登録日: 2021-02-12, 公開日: 2021-06-02, 最終更新日: 2023-10-18)

主引用文献

Wang, E.S.,Verano, A.L.,Nowak, R.P.,Yuan, J.C.,Donovan, K.A.,Eleuteri, N.A.,Yue, H.,Ngo, K.H.,Lizotte, P.H.,Gokhale, P.C.,Gray, N.S.,Fischer, E.S.
Acute pharmacological degradation of Helios destabilizes regulatory T cells.
Nat.Chem.Biol., 17:711-717, 2021

PubMed Abstract: The zinc-finger transcription factor Helios is critical for maintaining the identity, anergic phenotype and suppressive activity of regulatory T (T) cells. While it is an attractive target to enhance the efficacy of currently approved immunotherapies, no existing approaches can directly modulate Helios activity or abundance. Here, we report the structure-guided development of small molecules that recruit the E3 ubiquitin ligase substrate receptor cereblon to Helios, thereby promoting its degradation. Pharmacological Helios degradation destabilized the anergic phenotype and reduced the suppressive activity of T cells, establishing a route towards Helios-targeting therapeutics. More generally, this study provides a framework for the development of small-molecule degraders for previously unligandable targets by reprogramming E3 ligase substrate specificity.

PubMed: 34035522
DOI: 10.1038/s41589-021-00802-w

実験手法

X-RAY DIFFRACTION (3.78 Å)