biostudies-literatureFurihata HMEXT | Japan Society for the Promotion of Science4578https://www.ebi.ac.uk/biostudies/studies/S-EPMC7490372biostudies-literatureUnknown11(1)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 resiNature communicationsStructural bases of IMiD selectivity that emerges by 5-hydroxythalidomide.PMC7490372JP17J0844Miyakawa TFurihata HMiyauchi YSawasaki TYamanaka STanokura MAsano AShibata NHonda TfalseStructural bases of IMiD selectivity that emerges by 5-hydroxythalidomide.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 resi2020-01-01T00:00:00Z2020 Sep2026-05-03T20:33:50.201Z2020-10-08T07:16:45ZS-EPMC74903723292909010.1038/s41467-020-18488-4