Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide

Hirotake Furihata, Satoshi Yamanaka, Toshiaki Honda, Yumiko Miyauchi, Atsuko Asano, Norio Shibata, Masaru Tanokura (), Tatsuya Sawasaki () and Takuya Miyakawa ()
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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

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18488-4

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