5YJ1

Mouse Cereblon thalidomide binding domain complexed with R-form thalidomide

Summary for 5YJ1

• Entry DOI: 10.2210/pdb5yj1/pdb
• Related: 3WX2 5YIZ 5YJ0
• Descriptor: Protein cereblon, 2-[(3~{R})-2,6-bis(oxidanylidene)piperidin-3-yl]isoindole-1,3-dione, ZINC ION, ... (5 entities in total)
• Functional Keywords: zinc binding protein, metal binding protein
• Biological source: Mus musculus (Mouse)
• Cellular location: Cytoplasm : Q8C7D2
• Total number of polymer chains: 16
• Total formula weight: 205424.43

Authors

Mori, T.,Hakoshima, T. (deposition date: 2017-10-06, release date: 2018-02-07, Last modification date: 2023-11-22)

Primary citation

Mori, T.,Ito, T.,Liu, S.,Ando, H.,Sakamoto, S.,Yamaguchi, Y.,Tokunaga, E.,Shibata, N.,Handa, H.,Hakoshima, T.
Structural basis of thalidomide enantiomer binding to cereblon
Sci Rep, 8:1294-1294, 2018

PubMed Abstract: 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.

PubMed: 29358579
DOI: 10.1038/s41598-018-19202-7

Experimental method

X-RAY DIFFRACTION (2 Å)