A chemical 'on-switch', in which a small molecule mimics a natural activation mechanism of an enzyme, is described in a paper published online this week in Nature Chemical Biology.
There are many known kinase inhibitors, enzymes that help transfer phosphate groups from one molecule to another. However, chemicals that can activate kinases are rare and could be useful for treating certain diseases. Understanding how an 'activator' works may open up new avenues for drug discovery.When one kinase, PDK1, binds to a target kinase containing a phosphate group in a particular pocket, PDK1 changes to an active shape. Ricardo Biondi and colleagues now use structural and biochemical approaches to see how a chemical can activate PDK1 in the absence of the target kinase. They find that the chemical, despite being much smaller, causes the same structural changes in PDK1 as binding to the target kinase. As many kinases are activated by a similar approach, these results may provide a blueprint for designing chemical activators of other kinases.