A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase
| العنوان: | A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase |
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| المؤلفون: | 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 |
| المصدر: | Nature. 535:252-257 |
| بيانات النشر: | Springer Science and Business Media LLC, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| تدمد: | 1476-4687 0028-0836 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::91e627c880e58840f87057e76f90aa5d https://doi.org/10.1038/nature18611 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....91e627c880e58840f87057e76f90aa5d |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14764687 00280836 |
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