Details

Autor(en) / Beteiligte

• Matyskiela, Mary E
• Lu, Gang
• Ito, Takumi
• Pagarigan, Barbra
• Lu, Chin-Chun
• Miller, Karen
• Fang, Wei
• Wang, Nai-Yu
• Nguyen, Derek
• Houston, Jack
• Carmel, Gilles
• Tran, Tam
• Riley, Mariko
• Nosaka, Lyn'Al
• Lander, Gabriel C
• Gaidarova, Svetlana
• Xu, Shuichan
• Ruchelman, Alexander L
• Handa, Hiroshi
• Carmichael, James
• Daniel, Thomas O
• Cathers, Brian E
• Lopez-Girona, Antonia
• Chamberlain, Philip P

Titel

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

Ist Teil von

• Nature (London), 2016-07, Vol.535 (7611), p.252-257

Ort / Verlag

England

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.