Abstract
Thalidomide-dependent degradation of the embryonic transcription factor SALL4 by the CRL4CRBN 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.
Publication types
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Adaptor Proteins, Signal Transducing / chemistry*
-
Adaptor Proteins, Signal Transducing / genetics
-
Crystallography, X-Ray
-
DNA-Binding Proteins / chemistry
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / ultrastructure*
-
Humans
-
Multiprotein Complexes / chemistry
-
Multiprotein Complexes / genetics
-
Multiprotein Complexes / ultrastructure*
-
Protein Binding
-
Protein Conformation
-
Proteolysis / drug effects
-
Substrate Specificity
-
Thalidomide / analogs & derivatives
-
Thalidomide / chemistry
-
Thalidomide / pharmacology
-
Transcription Factors / chemistry
-
Transcription Factors / genetics
-
Transcription Factors / ultrastructure*
-
Ubiquitin-Protein Ligases / chemistry
-
Ubiquitin-Protein Ligases / ultrastructure
-
Ubiquitination / genetics
Substances
-
Adaptor Proteins, Signal Transducing
-
CRBN protein, human
-
DDB1 protein, human
-
DNA-Binding Proteins
-
Multiprotein Complexes
-
SALL4 protein, human
-
Transcription Factors
-
Thalidomide
-
pomalidomide
-
Ubiquitin-Protein Ligases