Crystal structure of thalidomide (yellow calotte model) bound to CRBN (green, blue and cyan) and DDB1 (yellow, grey, red and purple). (Source: FMI)
Scientists have clarified the workings of thalidomide at the molecular level. Their analysis of various structures indicates that the drug can interfere with cellular processes in two different ways-once preventing and once promoting protein degradation-thus explaining its diverse clinical effects. In the early 1960s, thalidomide - a drug widely prescribed at that time as a sedative and for the treatment of morning sickness in pregnancy - became notorious when it was found to cause birth defects. The product was subsequently withdrawn from the market. In the late 1990s, however, thalidomide and its derivatives were shown to be effective in the treatment of certain types of blood cancer, and the drug has come back into use - subject to strict safety requirements. In a study published in Nature , Nicolas Thomä and his group of structural biologists at the Friedrich Miescher Institute for Biomedical Research have now revealed how thalidomide interacts with its target protein in the cell, giving rise to the different kinds of clinical effects. Thalidomide has been known to interact with a large protein complex known as DDB1-CRBN.
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