Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide

• Published in: Nature communications 2020-09, Vol.11 (1), p.4578-11, Article 4578
• Main Authors: Furihata, Hirotake, Yamanaka, Satoshi, Honda, Toshiaki, Miyauchi, Yumiko, Asano, Atsuko, Shibata, Norio, Tanokura, Masaru, Sawasaki, Tatsuya, Miyakawa, Takuya
• Format: Article
• Language: English
• Subjects: 631/337/474/2073; 631/45/2783; 631/45/474/2073; 631/535; 631/92/609; Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - metabolism; Amino Acid Sequence; Complex formation; Crystal structure; Cytochrome; Cytochrome P450; Cytochromes P450; Enzymatic activity; HEK293 Cells; Humanities and Social Sciences; Humans; Immunologic Factors - chemistry; Immunologic Factors - pharmacology; Immunomodulation; Isoenzymes; Metabolism; Metabolites; Modulators; multidisciplinary; Mutagenesis; Proteasomes; Protein Binding - drug effects; Protein Domains; Science; Science (multidisciplinary); Selectivity; Stereoisomerism; Structural Homology, Protein; Substrate Specificity; Substrates; Teratogenicity; Thalidomide; Thalidomide - analogs & derivatives; Thalidomide - chemistry; Thalidomide - pharmacology; Transcription factors; Transcription Factors - chemistry; Transcription Factors - metabolism; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases; Zinc finger proteins
• ISSN: 2041-1723; 2041-1723
• 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. 5-hydroxythalidomide is a primary thalidomide metabolite generated by the cytochrome P450 isozymes. The reported data, including crystal structure of the 5-hydroxythalidomide-mediated complex of CRBN with SALL4, elucidate how additional hydroxy group of the metabolite enhances the interaction of CRBN with the neosubstrate SALL4.