5HXB

Cereblon in complex with DDB1, CC-885, and GSPT1

Summary for 5HXB

• Entry DOI: 10.2210/pdb5hxb/pdb
• Descriptor: Eukaryotic peptide chain release factor GTP-binding subunit ERF3A, DNA damage-binding protein 1, Protein cereblon, ... (5 entities in total)
• Functional Keywords: e3, ligase, ubiquitin, dcaf, cereblon, ddb1, crl4, cullin, imid, gspt1, crbn
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm: Q16531 Q96SW2
• Total number of polymer chains: 6
• Total formula weight: 392392.25

Authors

Chamberlain, P.P.,Matyskiela, M.,Pagarigan, B. (deposition date: 2016-01-30, release date: 2016-06-29, Last modification date: 2024-10-23)

Primary citation

Matyskiela, M.E.,Lu, G.,Ito, T.,Pagarigan, B.,Lu, C.C.,Miller, K.,Fang, W.,Wang, N.Y.,Nguyen, D.,Houston, J.,Carmel, G.,Tran, T.,Riley, M.,Nosaka, L.,Lander, G.C.,Gaidarova, S.,Xu, S.,Ruchelman, A.L.,Handa, H.,Carmichael, J.,Daniel, T.O.,Cathers, B.E.,Lopez-Girona, A.,Chamberlain, P.P.
A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase.
Nature, 535:252-257, 2016

PubMed 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.

PubMed: 27338790
DOI: 10.1038/nature18611

Experimental method

X-RAY DIFFRACTION (3.6 Å)