التفاصيل البيبلوغرافية
| العنوان: |
A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase |
| المؤلفون: |
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 |
| المصدر: |
Nature, Nature. 535(7611):252-257 |
| سنة النشر: |
2016 |
| الوصف: |
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. |
| نوع الوثيقة: |
redif-article |
| اللغة: |
English |
| DOI: |
10.1038/nature18611 |
| الإتاحة: |
https://ideas.repec.org/a/nat/nature/v535y2016i7611d10.1038_nature18611.html |
| رقم الأكسشن: |
edsrep.a.nat.nature.v535y2016i7611d10.1038.nature18611 |
| قاعدة البيانات: |
RePEc |
