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Updated: Dec 9, 2025
10:44
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
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Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide
Hirotake Furihata1, Satoshi Yamanaka2, Toshiaki Honda3
1Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan.
Nature Communications
|September 15, 2020
Summary
5-hydroxythalidomide, a metabolite of thalidomide, specifically targets SALL4 for proteasomal degradation. Structural analysis reveals how this metabolite binds to cereblon (CRBN), altering substrate specificity for immunomodulatory drugs (IMiDs).
Area of Science:
- Structural Biology
- Pharmacology
- Molecular Biology
Background:
- Thalidomide derivatives (IMiDs) have therapeutic and teratogenic effects.
- These effects are linked to interactions with C2H2 zinc-finger (ZF) transcription factors like SALL4.
- Metabolism of thalidomide produces compounds that can alter its interactions.
Purpose of the Study:
- To elucidate the structural basis of SALL4 proteasomal degradation induced by 5-hydroxythalidomide.
- To understand the interaction between 5-hydroxythalidomide, cereblon (CRBN), and SALL4.
- To investigate the molecular mechanisms behind the altered substrate specificity of thalidomide metabolites.
Main Methods:
- X-ray crystallography to determine the structure of the SALL4-CRBN complex.
- Mutagenesis studies to probe protein interactions.
- Analysis of metabolite-mediated protein degradation.
Main Results:
- The crystal structure reveals how 5-hydroxythalidomide bridges human SALL4 and CRBN.
- An additional hydroxyl group on (S)-5-hydroxythalidomide enhances CRBN binding.
- Variations in the SALL4 β-hairpin structure contribute to neosubstrate selectivity.
Conclusions:
- Metabolism-induced structural changes in IMiDs alter their substrate specificity.
- The findings provide structural insights into the mechanism of CRBN-based E3 ligase modulators.
- Understanding these interactions is crucial for developing safer and more effective IMiD therapies.
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