Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs (August 12, 2014)

Half a century has passed since the initial use of thalidomide caused a worldwide medical disaster, resulting in more than 10,000 babies with severe birth defects such as phocomelia with undeveloped limbs. Notwithstanding the growing clinical interest in the use of thalidomide and its derivatives as potential immunomodulatory drugs (IMiDs) now widely used in cancer therapy, the precise mechanism by which thalidomide discriminates its target protein Cereblon (CRBN) and exerts its specific actions remains unknown. CRBN forms the Cul4-Rbx1-DDB1-CRBN E3 ubiquitin ligase complex which is the target of thalidomide and its derivatives, lenalidomide and pomalidomide, therapeutically important drugs for multiple myeloma and other B-cell malignancies. The research groups of professor Hakoshima at the Structural Biology Laboratory of the Graduate School of Biological Sciences at the Nara Institute of Science and Technology (NAIST; President Naotake Ogasawara) and of professor Handa at Tokyo Medical University have performed an international collaboration with researchers at Celgene Corporation (San Diego, CA USA) and determined the crystal structure of human CRBN bound to DDB1 and lenalidomide, and the structures of the mouse TBD in the apo state and with thalidomide or pomalidomide. The structures revealed that a hydrophobic pocket in the thalidomide-binding domain of CRBN accommodates the glutarimide moiety of the drugs, whereas the isoindolinone ring is exposed to solvent (Fig. 1). Site-directed mutagenesis in lentiviral-expression myeloma models showed that key drug-binding residues are critical for antiproliferative effects. Our study provides a structural framework for further investigations on the mechanisms of the pharmaceutical and teratogenic actions of this drug and for the development of more effective thalidomide derivatives.

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