Host: The Japanese Society of Toxicology
Name : The 49th Annual Meeting of the Japanese Society of Toxicology
Date : June 30, 2022 - July 02, 2022
Cereblon (CRBN) is a component of E3 ubiquitin ligase that degrades target proteins (neosubstrates) in a thalidomide-dependent manner. C2H2 zinc finger (ZF)-type transcription factors are the largest family of known neosubstrates, of which IKZF1/IKZF3 and SALL4 are involved in the immunomodulatory and teratogenic effects of thalidomide, respectively. Recently, we revealed the mechanism by which a hydroxylated thalidomide metabolite at the C5 position of the phthalimide moiety (5-hydroxythalidomide, 5HT) efficiently triggers only the degradation of SALL4. Both thalidomide and 5HT served as "molecular glue" leading to the binding of the second ZF domain (ZF2) of SALL4 to CRBN. Although 5-hydroxylation of the phthalimide moiety did not change the binding position and orientation of thalidomide in the CRBN-SALL4 complex, it promoted the formation of a hydrogen-bonding network via water molecules. Furthermore, the hydroxy group of 5HT was located near theβ-hairpin structure of SALL4 ZF2 in the complex, and the second amino acid residue was found to be the key structural basis for the selectivity of 5HT for C2H2 ZF-type transcription factors. These findings suggest that the phthalimide moiety, which is affected by structural differences in C2H2 ZF-type transcription factors and in vivo metabolism, may be an effective target site for structure development to reduce the teratogenicity of thalidomide. In this symposium, we will also discuss the mechanism of species-specific teratogenicity of thalidomide based on the molecular structure of the CRBN-SALL4 complex.
