InterPro domain: IPR034750

The cereblon protein,originally identified in a screen for mutations causing mild mentalretardation, is a major target of thalidomide and its derivatives, and isresponsible for the teratogenic effects of the drug. Cereblon owes its name toits involvement in brain development and to its Lon N-terminal domain. Cereblon proteins occur throughout eukaryotes, however not infungi. Cereblon is a cofactor of damaged DNA-binding protein 1 (DDB1), whichacts as the central component of an E3 ubiquitin ligase complex and regulatesthe selective degradation of key proteins in DNA repair, replication andtranscription. Binding of thalidomide to a C-terminal region in cereblonalters the E3 ubiquitin ligase activity of the complex, which may in turncause its teratogenic effects. The thalidomide-binding region of cereblon is aconserved domain, CULT (for Cereblon domain of Unknown activity, bindingcellular Ligands and Thalidomide), carrying several invariant cysteine andtryptophan residues. The CULT domain is also found as the sole domain in afamily of secreted proteins from animals and in a family of bacterial proteinsoccurring primarily in gamma-proteobacteria. Given the invariant nature of theCULT domain between animals and bacteria, a natural ligand universal to alldomains of life seems plausible. The nature of the binding pocket, an aromaticcage of three tryptophan residues, suggests a role in the recognition ofcationic ligands [ 1 , 2 , 3 , 4 ].

The CULT domain is a member of the beta-tent fold, which consists of two four-stranded, antiparallel beta-sheets that are oriented at an approximately right angle and pinned together at the top via a structural zinc ion. The thalidomide binding site is formed within the larger, C-terminal beta-sheet. A third of the domain, including the thalidomide binding pocket, only folds upon ligand binding [ 5 , 5 , 5 , 5 ].

1. Thalidomide mimics uridine binding to an aromatic cage in cereblon. J. Struct. Biol. 188, 225-32
2. Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat. Struct. Mol. Biol. 21, 803-9
3. The thalidomide-binding domain of cereblon defines the CULT domain family and is a new member of the β-tent fold. PLoS Comput. Biol. 11, e1004023
4. Structural dynamics of the cereblon ligand binding domain. PLoS ONE 10, e0128342