Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide

In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4–RBX1–DDB1–CRBN (known as CRL4CRBN) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4CRBN. Here we present crystal structures of the DDB1–CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4CRBN and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4CRBN. Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4CRBN while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins. The crystal structures of thalidomide and its derivatives bound to the E3 ligase subcomplex DDB1–CRBN are shown; these drugs are found to have dual functions, interfering with the binding of certain cellular substrates to the E3 ligase but promoting the binding of others, thereby modulating the degradation of cellular proteins. Introduced in Europe in 1957 as a mild sedative, thalidomide was widely used in pregnant women as a treatment for morning sickness. This led to the birth of thousands of children with multiple defects and the drug was withdrawn in 1962. Since then thalidomide and its derivatives have emerged as effective treatments for the cancer multiple myeloma and the associated disorder 5q-dysplasia. The primary teratogenic target of thalidomide is cereblon (CRBN), part of E3 ubiquitin ligase complex CUL4–RBX1–DDB1–CRBN (CRL4CRBN). Here, Nicolas Thomä and colleagues present the crystal structure of DDB1–CRBN E3 ubiquitin ligase bound to thalidomide and to the related drugs lenalidomide and pomalidomide. The structure establishes the molecular mechanism underlying CRBN's enantioselective action. Further structure–function analysis reveals that these drugs have dual functions, interfering with the binding of certain cellular substrates to the E3 ligase but promoting the binding of others, thereby modulating the degradation of cellular proteins.