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

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. The structure of the second zinc finger of SALL4 in complex with pomalidomide, cereblon and DDB1 reveals the unique details of SALL4 recruitment, providing insights for rational design of cereblon-binding drugs with reduced teratogenic risk.