Thalidomide’s molecular actions revealed
July 16, 2014 § Leave a comment
Once shunned for causing severe birth defects in babies, thalidomide has made a comeback to treat some blood cancers and leprosy. In a paper now out in Nature, researchers describe the crystal structure of the drug bound to its target. From their data, the researchers provide an explanation how this drug can either save or wreck lives.
In the 1950s, women in Europe and other parts of the world were given the sedative thalidomide to battle morning sickness. But shortly thereafter, physicians realized that drug, which was marketed by a German company, caused limb deformities and other developmental problems in children. In 1961, the drug was withdrawn from the market. Nicolas Thomä at Friedrich Miescher Institute for Biomedical Research in Switzerland says that the notorious side effects of thalidomide were impossible to ignore when he was a child. “Born in Germany in the 1970s, I saw the teratogenic side effects of thalidomide,” he says. “I come from a small community and grew up with children who were directly affected by the drug.”
So in 2010, when another group of researchers demonstrated that thalidomide binds to a protein that’s part of a ubiquitin ligase complex, Thomä was doubly intrigued. His group long has been interested in ubiquitin ligases. Furthermore, conventional thinking had dictated to date that ubiquitin ligases couldn’t be targeted by drugs. But here was thalidomide, binding to a protein called CRBN. CRBN is a ubiquitously expressed protein that is part of a family of ubiquitin ligase complexes called CRL4; mutations in CRBN are associated with mental retardation. In 1998, the U.S. Food and Drug Administration approved the use of the drug to treat skin lesions caused by leprosy; in 2006, the agency extended its approval of thalidomide to treat multiple myeloma.
Thomä and his colleagues got down to work of figuring out how thalidomide interacted with CRBN. “As often is the case in crystallography, it took the right construct, the right conditions and a little bit of luck,” says Thomä, to get the structures of thalidomide and drugs like it bound to a complex of chicken CRBN (the chicken version closely resembles the human one) and its adaptor protein.
The investigators showed that when thalidomide bound to CRBN the protein was prevented from binding to one of its targets, the homeobox transcription factor MEIS2. However, when CRBN was bound with thalidomide the protein was able to associate with a different class of transcription factors, called Ikaros. In short, thalidomide was able to divert the CRBN’s function to new substrates like Ikaros at the cost of losing MEIS2 and possibly other native substrates. Thomä stresses that the investigators still don’t know which substrate causes thalidomide’s ugly side effects.
Overall, the investigators concluded that “thalidomide simultaneously acts as antagonist and agonist on CRL4, something that was previously unanticipated,” says Thomä. “The unexpected complexity of thalidomide action, acting simultaneously as inhibitor and agonist on the ubiquitin ligase, provides a molecular framework for how small molecules can be used as drugs to up- or downregulate cellular targets.”