7BQU

Cereblon in complex with SALL4 and (S)-thalidomide

7BQU の概要

• エントリーDOI: 10.2210/pdb7bqu/pdb
• 分子名称: Protein cereblon, Sal-like protein 4, S-Thalidomide, ... (5 entities in total)
• 機能のキーワード: zinc finger, e3 ubiquitin ligase, complex, thalidomide, metal binding protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 16134.24

構造登録者

Furihata, H.,Miyauchi, Y.,Asano, A.,Tanokura, M.,Miyakawa, T. (登録日: 2020-03-25, 公開日: 2020-08-26, 最終更新日: 2023-11-29)

主引用文献

Furihata, H.,Yamanaka, S.,Honda, T.,Miyauchi, Y.,Asano, A.,Shibata, N.,Tanokura, M.,Sawasaki, T.,Miyakawa, T.
Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide.
Nat Commun, 11:4578-4578, 2020

PubMed Abstract: Thalidomide and its derivatives exert not only therapeutic effects as immunomodulatory drugs (IMiDs) but also adverse effects such as teratogenicity, which are due in part to different C2H2 zinc-finger (ZF) transcription factors, IKZF1 (or IKZF3) and SALL4, respectively. Here, we report the structural bases for the SALL4-specific proteasomal degradation induced by 5-hydroxythalidomide, a primary thalidomide metabolite generated by the enzymatic activity of cytochrome P450 isozymes, through the interaction with cereblon (CRBN). The crystal structure of the metabolite-mediated human SALL4-CRBN complex and mutagenesis studies elucidate the complex formation enhanced by the interaction between CRBN and an additional hydroxy group of (S)-5-hydroxythalidomide and the variation in the second residue of β-hairpin structure that underlies the C2H2 ZF-type neo-morphic substrate (neosubstrate) selectivity of 5-hydroxythalidomide. These findings deepen our understanding of the pharmaceutical action of IMiDs and provide structural evidence that the glue-type E3 ligase modulators cause altered neosubstrate specificities through their metabolism.

PubMed: 32929090
DOI: 10.1038/s41467-020-18488-4

実験手法

X-RAY DIFFRACTION (1.9 Å)