6H0F

Structure of DDB1-CRBN-pomalidomide complex bound to IKZF1(ZF2)

6H0F の概要

• エントリーDOI: 10.2210/pdb6h0f/pdb
• 分子名称: DNA damage-binding protein 1,DNA damage-binding protein 1,DNA damage-binding protein 1,DNA damage-binding protein 1, Protein cereblon, DNA-binding protein Ikaros, ... (6 entities in total)
• 機能のキーワード: e3 ubiquitin ligase, drug mediated protein-interaction, targeted protein degradation, signaling protein
• 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: 597390.68

構造登録者

Petzold, G.,Bunker, R.D.,Thoma, N.H. (登録日: 2018-07-09, 公開日: 2018-11-07, 最終更新日: 2024-01-17)

主引用文献

Sievers, Q.L.,Petzold, G.,Bunker, R.D.,Renneville, A.,Slabicki, M.,Liddicoat, B.J.,Abdulrahman, W.,Mikkelsen, T.,Ebert, B.L.,Thoma, N.H.
Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN.
Science, 362:eaat0572-, 2018

PubMed Abstract: The small molecules thalidomide, lenalidomide, and pomalidomide induce the ubiquitination and proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) by recruiting a Cys-His (C2H2) zinc finger domain to Cereblon (CRBN), the substrate receptor of the CRL4 E3 ubiquitin ligase. We screened the human C2H2 zinc finger proteome for degradation in the presence of thalidomide analogs, identifying 11 zinc finger degrons. Structural and functional characterization of the C2H2 zinc finger degrons demonstrates how diverse zinc finger domains bind the permissive drug-CRBN interface. Computational zinc finger docking and biochemical analysis predict that more than 150 zinc fingers bind the drug-CRBN complex in vitro, and we show that selective zinc finger degradation can be achieved through compound modifications. Our results provide a rationale for therapeutically targeting transcription factors that were previously considered undruggable.

PubMed: 30385546
DOI: 10.1126/science.aat0572

実験手法

X-RAY DIFFRACTION (3.25 Å)