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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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Autores principales: Mori, Tomoyuki, Ito, Takumi, Liu, Shujie, Ando, Hideki, Sakamoto, Satoshi, Yamaguchi, Yuki, Tokunaga, Etsuko, Shibata, Norio, Handa, Hiroshi, Hakoshima, Toshio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778007/
https://www.ncbi.nlm.nih.gov/pubmed/29358579
http://dx.doi.org/10.1038/s41598-018-19202-7
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author Mori, Tomoyuki
Ito, Takumi
Liu, Shujie
Ando, Hideki
Sakamoto, Satoshi
Yamaguchi, Yuki
Tokunaga, Etsuko
Shibata, Norio
Handa, Hiroshi
Hakoshima, Toshio
author_facet Mori, Tomoyuki
Ito, Takumi
Liu, Shujie
Ando, Hideki
Sakamoto, Satoshi
Yamaguchi, Yuki
Tokunaga, Etsuko
Shibata, Norio
Handa, Hiroshi
Hakoshima, Toshio
author_sort Mori, Tomoyuki
collection PubMed
description 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.
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spelling pubmed-57780072018-01-31 Structural basis of thalidomide enantiomer binding to cereblon Mori, Tomoyuki Ito, Takumi Liu, Shujie Ando, Hideki Sakamoto, Satoshi Yamaguchi, Yuki Tokunaga, Etsuko Shibata, Norio Handa, Hiroshi Hakoshima, Toshio Sci Rep Article 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. Nature Publishing Group UK 2018-01-22 /pmc/articles/PMC5778007/ /pubmed/29358579 http://dx.doi.org/10.1038/s41598-018-19202-7 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Mori, Tomoyuki
Ito, Takumi
Liu, Shujie
Ando, Hideki
Sakamoto, Satoshi
Yamaguchi, Yuki
Tokunaga, Etsuko
Shibata, Norio
Handa, Hiroshi
Hakoshima, Toshio
Structural basis of thalidomide enantiomer binding to cereblon
title Structural basis of thalidomide enantiomer binding to cereblon
title_full Structural basis of thalidomide enantiomer binding to cereblon
title_fullStr Structural basis of thalidomide enantiomer binding to cereblon
title_full_unstemmed Structural basis of thalidomide enantiomer binding to cereblon
title_short Structural basis of thalidomide enantiomer binding to cereblon
title_sort structural basis of thalidomide enantiomer binding to cereblon
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778007/
https://www.ncbi.nlm.nih.gov/pubmed/29358579
http://dx.doi.org/10.1038/s41598-018-19202-7
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