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Protein kinases are major drug targets, but the development of highly-selective inhibitors has been challenging due to the similarity of their active sites. The observation of distinct structural states of the fully-conserved Asp-Phe-Gly (DFG) loop has put the concept of conformational selection for the DFG-state at the center of kinase drug discovery. Recently, it was shown that Gleevec selectivity for the Tyr-kinase Abl was instead rooted in conformational changes after drug binding. Here, we investigate whether protein dynamics after binding is a more general paradigm for drug selectivity by characterizing the binding of several approved drugs to the Ser/Thr-kinase Aurora A. Using a combination of biophysical techniques, we propose a universal drug-binding mechanism, that rationalizes selectivity, affinity and long on-target residence time for kinase inhibitors. These new concepts, where protein dynamics in the drug-bound state plays the crucial role, can be applied to inhibitor design of targets outside the kinome., eLife digest Protein kinases are a family of enzymes found in all living organisms. These enzymes help to control many biological processes, including cell division. When particular protein kinases do not work correctly, cells may start to divide uncontrollably, which can lead to cancer. One example is the kinase Aurora A, which is over-active in many common human cancers. As a result, researchers are currently trying to design drugs that reduce the activity of Aurora A in the hope that these could form new anticancer treatments. In general, drugs are designed to be as specific in their action as possible to reduce the risk of harmful side effects to the patient. Designing a drug that affects a single protein kinase, however, is difficult because there are hundreds of different kinases in the body, all with similar structures. Because drugs often work by binding to specific structural features, a drug that targets one protein kinase can often alter the activity of a large number of others too. Gleevec is a successful anti-leukemia drug that specifically works on one target kinase, producing minimal side effects. It was recently discovered that the drug works through a phenomenon called ‘induced fit’. This means that after the drug binds it causes a change in the enzyme’s overall shape that alters the activity of the enzyme. The shape change is complex, and so even small structural differences can change the effect of a particular drug. Do other drugs that target other protein kinases also produce induced fit effects? To find out, Pitsawong, Buosi, Otten, Agafonov et al. studied how three anti-cancer drugs interact with Aurora A: two drugs specifically designed to switch off Aurora A, and Gleevec (which does not target Aurora A). The two drugs that specifically target Aurora A were thought to work by targeting one structural feature of the enzyme. However, the biochemical and biophysical experiments performed by Pitsawong et al. revealed that these drugs instead work through an induced fit effect. By contrast, Gleevec did not trigger an induced fit on Aurora A and so bound less tightly to it. In light of these results, Pitsawong et al. suggest that future efforts to design drugs that target protein kinases should focus on exploiting the induced fit process. This will require more research into the structure of particular kinases.