5HXB: Cereblon in complex with DDB1, CC-885, and GSPT1

Citation:
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.
PDB ID: 5HXBDownload
MMDB ID: 140537
PDB Deposition Date: 2016/1/30
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 3.6  Å
Source Organism:
Similar Structures:
Biological Unit for 5HXB: trimeric; determined by author
Molecular Components in 5HXB
Label Count Molecule
Proteins (3 molecules)
1
Eukaryotic Peptide Chain Release Factor Gtp-binding Subunit Erf3a(Gene symbol: GSPT1)
Molecule annotation
1
DNA Damage-binding Protein 1(Gene symbol: DDB1)
Molecule annotation
1
Protein Cereblon(Gene symbol: CRBN)
Molecule annotation
Chemicals (2 molecules)
1
1
2
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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