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Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide

Author

Listed:
  • Hirotake Furihata

    (The University of Tokyo)

  • Satoshi Yamanaka

    (Ehime University)

  • Toshiaki Honda

    (Nagoya Institute of Technology)

  • Yumiko Miyauchi

    (The University of Tokyo)

  • Atsuko Asano

    (The University of Tokyo)

  • Norio Shibata

    (Nagoya Institute of Technology)

  • Masaru Tanokura

    (The University of Tokyo)

  • Tatsuya Sawasaki

    (Ehime University)

  • Takuya Miyakawa

    (The University of Tokyo)

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.

Suggested Citation

  • Hirotake Furihata & Satoshi Yamanaka & Toshiaki Honda & Yumiko Miyauchi & Atsuko Asano & Norio Shibata & Masaru Tanokura & Tatsuya Sawasaki & Takuya Miyakawa, 2020. "Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18488-4
    DOI: 10.1038/s41467-020-18488-4
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    Cited by:

    1. Satoshi Yamanaka & Hirotake Furihata & Yuta Yanagihara & Akihito Taya & Takato Nagasaka & Mai Usui & Koya Nagaoka & Yuki Shoya & Kohei Nishino & Shuhei Yoshida & Hidetaka Kosako & Masaru Tanokura & Ta, 2023. "Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Shiyun Cao & Shoukai Kang & Haibin Mao & Jiayu Yao & Liangcai Gu & Ning Zheng, 2022. "Defining molecular glues with a dual-nanobody cannabidiol sensor," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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