A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase
| Autor: | Alexander L. Ruchelman, Jack Houston, Nai-Yu Wang, Lyn'Al Nosaka, Antonia Lopez-Girona, Takumi Ito, Gilles Carmel, Mary E Matyskiela, Wei Fang, Derek Nguyen, Philip P Chamberlain, Thomas O. Daniel, Karen Miller, Chin-Chun Lu, Barbra Pagarigan, Svetlana Gaidarova, Gang Lu, Shuichan Xu, James Carmichael, Tam Tran, Gabriel C. Lander, Mariko Riley, Brian E. Cathers, Hiroshi Handa |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Ubiquitin-Protein Ligases Amino Acid Motifs Antineoplastic Agents Plasma protein binding Crystallography X-Ray 01 natural sciences DNA-binding protein Substrate Specificity Ikaros Transcription Factor 03 medical and health sciences Ubiquitin Humans Adaptor Proteins Signal Transducing chemistry.chemical_classification DNA ligase Binding Sites Multidisciplinary biology 010405 organic chemistry Chemistry Phenylurea Compounds Cereblon Thalidomide 0104 chemical sciences Ubiquitin ligase Cell biology DNA-Binding Proteins 030104 developmental biology Multiprotein Complexes Proteolysis biology.protein Degron Peptide Hydrolases Peptide Termination Factors Protein Binding |
| Zdroj: | Nature. 535:252-257 |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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