3WX2

Mouse Cereblon thalidomide binding domain, native


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.197 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs

Chamberlain, P.P.Lopez-Girona, A.Miller, K.Carmel, G.Pagarigan, B.Chie-Leon, B.Rychak, E.Corral, L.G.Ren, Y.J.Wang, M.Riley, M.Delker, S.L.Ito, T.Ando, H.Mori, T.Hirano, Y.Handa, H.Hakoshima, T.Daniel, T.O.Cathers, B.E.

(2014) Nat Struct Mol Biol 21: 803-809

  • DOI: https://doi.org/10.1038/nsmb.2874
  • Primary Citation of Related Structures:  
    3WX1, 3WX2

  • PubMed Abstract: 

    The Cul4-Rbx1-DDB1-Cereblon E3 ubiquitin ligase complex is the target of thalidomide, lenalidomide and pomalidomide, therapeutically important drugs for multiple myeloma and other B-cell malignancies. These drugs directly bind Cereblon (CRBN) and promote the recruitment of substrates Ikaros (IKZF1) and Aiolos (IKZF3) to the E3 complex, thus leading to substrate ubiquitination and degradation. Here we present the crystal structure of human CRBN bound to DDB1 and the drug lenalidomide. A hydrophobic pocket in the thalidomide-binding domain (TBD) of CRBN accommodates the glutarimide moiety of lenalidomide, whereas the isoindolinone ring is exposed to solvent. We also solved the structures of the mouse TBD in the apo state and with thalidomide or pomalidomide. Site-directed mutagenesis in lentiviral-expression myeloma models showed that key drug-binding residues are critical for antiproliferative effects.


  • Organizational Affiliation

    Celgene Corporation, San Diego, California, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protein cereblon
A, B
111Mus musculusMutation(s): 0 
Gene Names: Crbn
UniProt & NIH Common Fund Data Resources
Find proteins for Q8C7D2 (Mus musculus)
Explore Q8C7D2 
Go to UniProtKB:  Q8C7D2
IMPC:  MGI:1913277
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8C7D2
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.197 
  • Space Group: I 21 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 117.726α = 90
b = 117.726β = 90
c = 117.726γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-08-06
    Type: Initial release
  • Version 1.1: 2014-08-27
    Changes: Database references
  • Version 1.2: 2014-09-17
    Changes: Database references
  • Version 1.3: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description