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Identification of a primary target of thalidomide teratogenicity

Integrated Research Institute, Tokyo Institute of Technology, Yokohama 226-8503, Japan.
Science (Impact Factor: 31.48). 03/2010; 327(5971):1345-50. DOI: 10.1126/science.1177319
Source: PubMed

ABSTRACT Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects. Today, thalidomide is still used in the treatment of leprosy and multiple myeloma, although how it causes limb malformation and other developmental defects is unknown. Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity. This study reveals a basis for thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity.

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    • "Recently, the crystal structure of DDB1-CRBN E3 ubiquitin ligase in complex with THAL/LEN has been described [13] [14]. CBMs bind at the C terminus of CRBN in a small hydrophobic pocket composed of three tryptophan residues (Trp380, Trp386 and Trp400) [13] and mutations in these residues have been demonstrated to cause CBM resistance [2] [10] [15]. This thalidomide binding domain (TBD) is highly conserved across species, however four amino acids differ between mouse and human proteins, most likely explaining lack of rodent responsiveness to IMiDs [13]. "
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