IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v535y2016i7611d10.1038_nature18611.html
   My bibliography  Save this article

A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase

Author

Listed:
  • Mary E. Matyskiela

    (Celgene Corporation)

  • Gang Lu

    (Celgene Corporation)

  • Takumi Ito

    (Tokyo Medical University)

  • Barbra Pagarigan

    (Celgene Corporation)

  • Chin-Chun Lu

    (Celgene Corporation)

  • Karen Miller

    (Celgene Corporation)

  • Wei Fang

    (Celgene Corporation)

  • Nai-Yu Wang

    (Celgene Corporation)

  • Derek Nguyen

    (Celgene Corporation)

  • Jack Houston

    (Celgene Corporation)

  • Gilles Carmel

    (Celgene Corporation)

  • Tam Tran

    (Celgene Corporation)

  • Mariko Riley

    (Celgene Corporation)

  • Lyn’Al Nosaka

    (The Scripps Research Institute)

  • Gabriel C. Lander

    (The Scripps Research Institute)

  • Svetlana Gaidarova

    (Celgene Corporation)

  • Shuichan Xu

    (Celgene Corporation)

  • Alexander L. Ruchelman

    (Celgene Corporation)

  • Hiroshi Handa

    (Tokyo Medical University)

  • James Carmichael

    (Celgene Corporation)

  • Thomas O. Daniel

    (Celgene Corporation)

  • Brian E. Cathers

    (Celgene Corporation)

  • Antonia Lopez-Girona

    (Celgene Corporation)

  • Philip P. Chamberlain

    (Celgene Corporation)

Abstract

Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4CRBN E3 ubiquitin ligase. Here we report the identification of a new cereblon modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism. Crystallographic studies of the CRBN–DDB1–CC-885–GSPT1 complex reveal that GSPT1 binds to cereblon through a surface turn containing a glycine residue at a key position, interacting with both CC-885 and a ‘hotspot’ on the cereblon surface. Although GSPT1 possesses no obvious structural, sequence or functional homology to previously known cereblon substrates, mutational analysis and modelling indicate that the cereblon substrate Ikaros uses a similar structural feature to bind cereblon, suggesting a common motif for substrate recruitment. These findings define a structural degron underlying cereblon ‘neosubstrate’ selectivity, and identify an anti-tumour target rendered druggable by cereblon modulation.

Suggested Citation

  • Mary E. Matyskiela & Gang Lu & Takumi Ito & Barbra Pagarigan & Chin-Chun Lu & Karen Miller & Wei Fang & Nai-Yu Wang & Derek Nguyen & Jack Houston & Gilles Carmel & Tam Tran & Mariko Riley & Lyn’Al Nos, 2016. "A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase," Nature, Nature, vol. 535(7611), pages 252-257, July.
  • Handle: RePEc:nat:nature:v:535:y:2016:i:7611:d:10.1038_nature18611
    DOI: 10.1038/nature18611
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/nature18611
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/nature18611?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Satoshi Yamanaka & Hirotake Furihata & Yuta Yanagihara & Akihito Taya & Takato Nagasaka & Mai Usui & Koya Nagaoka & Yuki Shoya & Kohei Nishino & Shuhei Yoshida & Hidetaka Kosako & Masaru Tanokura & Ta, 2023. "Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Jian Ma & Lei Li & Bohan Ma & Tianjie Liu & Zixi Wang & Qi Ye & Yunhua Peng & Bin Wang & Yule Chen & Shan Xu & Ke Wang & Fabin Dang & Xinyang Wang & Zixuan Zeng & Yanlin Jian & Zhihua Ren & Yizeng Fan, 2024. "MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Gisele Nishiguchi & Lauren G. Mascibroda & Sarah M. Young & Elizabeth A. Caine & Sherif Abdelhamed & Jeffrey J. Kooijman & Darcie J. Miller & Sourav Das & Kevin McGowan & Anand Mayasundari & Zhe Shi &, 2024. "Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Alena Kroupova & Valentina A. Spiteri & Zoe J. Rutter & Hirotake Furihata & Darren Darren & Sarath Ramachandran & Sohini Chakraborti & Kevin Haubrich & Julie Pethe & Denzel Gonzales & Andre J. Wijaya , 2024. "Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Zefeng Wang & Shabnam Shaabani & Xiang Gao & Yuen Lam Dora Ng & Valeriia Sapozhnikova & Philipp Mertins & Jan Krönke & Alexander Dömling, 2023. "Direct-to-biology, automated, nano-scale synthesis, and phenotypic screening-enabled E3 ligase modulator discovery," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    6. Zemin Zhang & Yuanqing Li & Jie Yang & Jiacheng Li & Xiongqiang Lin & Ting Liu & Shiling Yang & Jin Lin & Shengyu Xue & Jiamin Yu & Cailing Tang & Ziteng Li & Liping Liu & Zhengzheng Ye & Yanan Deng &, 2024. "Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    7. Shiyun Cao & Shoukai Kang & Haibin Mao & Jiayu Yao & Liangcai Gu & Ning Zheng, 2022. "Defining molecular glues with a dual-nanobody cannabidiol sensor," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:535:y:2016:i:7611:d:10.1038_nature18611. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.