Structural basis of thalidomide enantiomer binding to cereblon

Thalidomide possesses two optical isomers which have been reported to exhibit different pharmacological and toxicological activities. However, the precise mechanism by which the two isomers exert their different activities remains poorly understood. Here, we present structural and biochemical studie...

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Bibliographic Details
Published in:Scientific reports 2018-01, Vol.8 (1), p.1294-14, Article 1294
Main Authors: Mori, Tomoyuki, Ito, Takumi, Liu, Shujie, Ando, Hideki, Sakamoto, Satoshi, Yamaguchi, Yuki, Tokunaga, Etsuko, Shibata, Norio, Handa, Hiroshi, Hakoshima, Toshio
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Animal Fins - abnormalities
Animal Fins - drug effects
Animal Fins - growth & development
Animals
Binding Sites
Cloning, Molecular
Conformation
Crystal structure
Crystallography, X-Ray
Embryo, Nonmammalian
Enantiomers
Escherichia coli - genetics
Escherichia coli - metabolism
Fins
Gene Expression
Isomers
Mice
Molecular Docking Simulation
Nerve Tissue Proteins - antagonists & inhibitors
Nerve Tissue Proteins - chemistry
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Protein Binding
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Protein Processing, Post-Translational
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Stereoisomerism
Teratogenicity
Teratogens - chemistry
Teratogens - metabolism
Teratogens - pharmacology
Thalidomide
Thalidomide - chemistry
Thalidomide - metabolism
Thalidomide - pharmacology
Thermodynamics
Ubiquitin
Ubiquitination
Zebrafish
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Summary:Thalidomide possesses two optical isomers which have been reported to exhibit different pharmacological and toxicological activities. However, the precise mechanism by which the two isomers exert their different activities remains poorly understood. Here, we present structural and biochemical studies of (S)- and (R)-enantiomers bound to the primary target of thalidomide, cereblon (CRBN). Our biochemical studies employed deuterium-substituted thalidomides to suppress optical isomer conversion, and established that the (S)-enantiomer exhibited ~10-fold stronger binding to CRBN and inhibition of self-ubiquitylation compared to the (R)-enantiomer. The crystal structures of the thalidomide-binding domain of CRBN bound to each enantiomer show that both enantiomers bind the tri-Trp pocket, although the bound form of the (S)-enantiomer exhibited a more relaxed glutarimide ring conformation. The (S)-enantiomer induced greater teratogenic effects on fins of zebrafish compared to the (R)-enantiomer. This study has established a mechanism by which thalidomide exerts its effects in a stereospecific manner at the atomic level.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-19202-7