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Researchers have found that the drug thalidomide works in an unexpectedly complex way. Originally banned for causing birth defects when administered to pregnant women as a sedative, thalidomide was subsequently discovered to have anticancer effects and is now an approved medication. But its mechanism of action has remained unknown. In 2010, Hiroshi Handa of Tokyo Institute of Technology and coworkers found that its biological target is cereblon, a component of an E3 ubiquitin ligase complex called CRL4CRBN that marks substrates for degradation. Now, Nicolas H. Thomä of the Friedrich Miescher Institute for Biomedical Research, in Basel, and coworkers have obtained crystal structures of thalidomide or derivatives bound to cereblon, enabling them to characterize the drug’s mechanism (Nature 2014, DOI: 10.1038/nature13527). When thalidomide binds cereblon, it inhibits the ligase’s normal activity by preventing endogenous substrates from binding, protecting them from degradation. But it also recruits the transcription factors IKZF1 and IKZF3 to the enzyme’s active site, promoting their degradation. The work could help lead to the discovery of other small molecules that modulate the ligase complex in a similar dual manner, the researchers note.
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