6UML

Structural Basis for Thalidomide Teratogenicity Revealed by the Cereblon-DDB1-SALL4-Pomalidomide Complex

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.58 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.207 

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This is version 1.2 of the entry. See complete history. 


Literature

Crystal structure of the SALL4-pomalidomide-cereblon-DDB1 complex.

Matyskiela, M.E., Clayton, T., Zheng, X., Mayne, C., Tran, E., Carpenter, A., Pagarigan, B., McDonald, J., Rolfe, M., Hamann, L.G., Lu, G., Chamberlain, P.P.

(2020) Nat Struct Mol Biol 27: 319-322

  • DOI: https://doi.org/10.1038/s41594-020-0405-9
  • Primary Citation of Related Structures:  
    6UML

  • PubMed Abstract: 

    Thalidomide-dependent degradation of the embryonic transcription factor SALL4 by the CRL4 CRBN E3 ubiquitin ligase is a plausible major driver of thalidomide teratogenicity. The structure of the second zinc finger of SALL4 in complex with pomalidomide, cereblon and DDB1 reveals the molecular details of recruitment. Sequence differences and a shifted binding position relative to Ikaros offer a path to the rational design of cereblon-binding drugs with reduced teratogenic risk.

    • Organizational Affiliation: 

    Celgene Corporation, San Diego, CA, USA. mmatyskiela@celgene.com.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DNA damage-binding protein 11,140Homo sapiensMutation(s): 0 
Gene Names: DDB1, XAP1
UniProt & NIH Common Fund Data Resources
Find proteins for Q16531 (Homo sapiens)
Explore Q16531 
Go to UniProtKB:  Q16531
PHAROS:  Q16531
GTEx:  ENSG00000167986 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ16531
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Protein cereblonB [auth C]406Homo sapiensMutation(s): 0 
Gene Names: CRBN, AD-006
UniProt & NIH Common Fund Data Resources
Find proteins for Q96SW2 (Homo sapiens)
Explore Q96SW2 
Go to UniProtKB:  Q96SW2
PHAROS:  Q96SW2
GTEx:  ENSG00000113851 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ96SW2
Sequence Annotations
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  • Reference Sequence
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(by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Sal-like protein 4C [auth E]28Homo sapiensMutation(s): 0 
Gene Names: SALL4, ZNF797
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UJQ4 (Homo sapiens)
Explore Q9UJQ4 
Go to UniProtKB:  Q9UJQ4
PHAROS:  Q9UJQ4
GTEx:  ENSG00000101115 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9UJQ4
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.58 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.207 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.409α = 90
b = 127.725β = 109.694
c = 110.174γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
xia2data reduction
DIALSdata scaling
PHASERphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2020-04-15
    Type: Initial release
  • Version 1.1: 2020-04-22
    Changes: Database references
  • Version 1.2: 2023-10-11
    Changes: Data collection, Database references, Refinement description