2020年9月14日
Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide.
Nature communications
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- 巻
- 11
- 号
- 1
- 開始ページ
- 4578
- 終了ページ
- 4578
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1038/s41467-020-18488-4
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.
- リンク情報
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- DOI
- https://doi.org/10.1038/s41467-020-18488-4
- PubMed
- https://www.ncbi.nlm.nih.gov/pubmed/32929090
- PubMed Central
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490372
- 共同研究・競争的資金等の研究課題
- 無細胞ヒトプロテインアレイを用いた薬剤依存的相互作用タンパク質同定技術の開発
- 共同研究・競争的資金等の研究課題
- コムギ無細胞系による構造解析に適した複合体タンパク質生産・調製技術と低分子抗体作製技術の創出
- 共同研究・競争的資金等の研究課題
- 分子間相互作用に基づくシグナル伝達網解析のための無細胞プロテオーム技術の開発
- ID情報
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- DOI : 10.1038/s41467-020-18488-4
- PubMed ID : 32929090
- PubMed Central 記事ID : PMC7490372