Abstract
Thalidomide and its derivatives lenalidomide and pomalidomide are important anticancer agents but can cause severe birth defects via an interaction with the protein cereblon. The ligand-binding domain of cereblon is found, with a high degree of conservation, in both bacteria and eukaryotes. Using a bacterial model system, we reveal the structural determinants of cereblon substrate recognition, based on a series of high-resolution crystal structures. For the first time, we identify a cellular ligand that is universally present: we show that thalidomide and its derivatives mimic and compete for the binding of uridine, and validate these findings in vivo. The nature of the binding pocket, an aromatic cage of three tryptophan residues, further suggests a role in the recognition of cationic ligands. Our results allow for general evaluation of pharmaceuticals for potential cereblon-dependent teratogenicity.
Highlights
Thalidomide was originally introduced for its sedative and anti-emetic properties in the 1950s, but banned from the market in the early 1960s due to teratogenic effects that had led to severe developmental defects in about 10,000 newborns
They showed that cereblon associates with damaged DNA binding protein 1 (DDB1), a core component of the DDB1/cullin4 (CUL4) E3 ubiquitin ligase complex which is known as a key player in the nucleotide excision repair pathway
To confirm that MsCI4 binds to thalidomide, we employed a simple NMRbased assay that relies on chemical shift changes that occur upon ligand binding
Summary
Thalidomide was originally introduced for its sedative and anti-emetic properties in the 1950s, but banned from the market in the early 1960s due to teratogenic effects that had led to severe developmental defects in about 10,000 newborns. Of thalidomide (Ito et al, 2010) They showed that cereblon associates with damaged DNA binding protein 1 (DDB1), a core component of the DDB1/cullin (CUL4) E3 ubiquitin ligase complex which is known as a key player in the nucleotide excision repair pathway. Searches for distant homologs show that the CULT domain is related to proteins sharing a common fold formed by two fourstranded, antiparallel b-sheets that are oriented at approximately a right angle, and pinned together at their tip by a zinc ion (Lupas et al, 2014) We have named this fold the b-tent for the prominent arrangement of its b-sheets. Substantiated by an NMRbased assay and in vivo data, the structures provide the molecular basis for thalidomide teratogenicity and, for the first time, reveal potential natural ligands that are universally present in all organisms with cereblon proteins
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
