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A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase

Academic Article
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Overview

authors

  • Matyskiela, M. E.
  • Lu, G.
  • Ito, T.
  • Pagarigan, B.
  • Lu, C. C.
  • Miller, Karen
  • Fang, W.
  • Wang, N. Y.
  • Nguyen, D.
  • Houston, J.
  • Carmel, G.
  • Tran, T.
  • Riley, M.
  • Nosaka, L.
  • Lander, Gabriel
  • Gaidarova, S.
  • Xu, S.
  • Ruchelman, A. L.
  • Handa, H.
  • Carmichael, J.
  • Daniel, T. O.
  • Cathers, B. E.
  • Lopez-Girona, A.
  • Chamberlain, P. P.

publication date

  • July 2016

journal

  • Nature  Journal

abstract

  • Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4(CRBN) 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.

subject areas

  • Amino Acid Motifs
  • Antineoplastic Agents
  • Binding Sites
  • Crystallography, X-Ray
  • DNA-Binding Proteins
  • Humans
  • Ikaros Transcription Factor
  • Models, Molecular
  • Multiprotein Complexes
  • Peptide Hydrolases
  • Peptide Termination Factors
  • Phenylurea Compounds
  • Protein Binding
  • Proteolysis
  • Substrate Specificity
  • Thalidomide
  • Ubiquitin-Protein Ligases
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Identity

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature18611

PubMed ID

  • 27338790
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Additional Document Info

start page

  • 252

end page

  • 257

volume

  • 535

issue

  • 7611

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