4V2Y

Cereblon isoform 4 from Magnetospirillum gryphiswaldense in complex with Thalidomide

Summary for 4V2Y

• Entry DOI: 10.2210/pdb4v2y/pdb
• Related: 4V2Z 4V30 4V31 4V32
• Descriptor: CEREBLON ISOFORM 4, ZINC ION, S-Thalidomide, ... (4 entities in total)
• Functional Keywords: signaling protein, teratogenicity, aromatic cage
• Biological source: MAGNETOSPIRILLUM GRYPHISWALDENSE
• Total number of polymer chains: 3
• Total formula weight: 42081.64

Authors

Hartmann, M.D.,Lupas, A.N.,Hernandez Alvarez, B. (deposition date: 2014-10-15, release date: 2014-12-17, Last modification date: 2024-05-08)

Primary citation

Hartmann, M.D.,Boichenko, I.,Coles, M.,Zanini, F.,Lupas, A.N.,Hernandez Alvarez, B.
Thalidomide Mimics Uridine Binding to an Aromatic Cage in Cereblon.
J.Struct.Biol., 188:225-, 2014

PubMed 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.

PubMed: 25448889
DOI: 10.1016/J.JSB.2014.10.010

Experimental method

X-RAY DIFFRACTION (1.4 Å)