Nature doi:10.1038/nature13527

Thalidomide and its derivatives lenalidomide and pomalidomide interact with cereblon (CRBN), a substrate recognition component of the Cul4 ubiquitin E3 ligase complex, to promote the ubiquitin-dependent degradation of two members of the Ikaros family of transcription factors, IKZF1 and IKZF3. However, the location of the thalidomide-interacting site on CRBN was not known. Fischer et al. obtained crystal structures of a Cul4 complex component made up of the human DDB1–chicken CRBN co-complex with thalidomide and its derivatives. The S enantiomer of all three compounds bound a conserved pocket on the C-terminal domain of CRBN and required their glutarimide moiety for proper engagement. Thalidomide occupation on CRBN was known to be required for IKZF1 and IKZF3 degradation, but its effect on endogenous substrates was unknown. To identify these, the authors performed a biochemical screen and identified the homeobox transcription factor MEIS2, which is involved in brain and eye development, as a target for ubiquitination. In this case, ubiquitin-mediated degradation of MEIS2 was blocked upon treatment with lenalidomide. Multiple lines of evidence on the biochemical and cellular levels support the finding that lenalidomide and MEIS2 compete for the same binding site. The binding of thalidomide-like derivatives to CRBN prevents access to endogenous CRBN substrates such as MEIS2, resulting in their stabilization while promoting the degradation of IKZF1 and IKZF2. Overall, thalidomide-like derivatives can modulate both the stability and degradation of particular proteins.