The leukemia drug Gleevec is exquisitely selective. It binds strongly to and inhibits a kinase enzyme known as Abl but doesn’t bind much to the closely related enzyme Src. Scientists have not been able to account for the 3,000-fold difference in binding affinity for the two kinases. To understand Gleevec’s preference, Dorothee Kern and coworkers at Brandeis University reconstructed Abl and Src’s last common ancestral protein and other proteins along the evolutionary paths leading to the modern kinases (Science 2015, DOI: 10.1126/science.aaa1823). The ancestral protein binds Gleevec with an affinity between that of Abl and Src. The affinity increased along the evolutionary trail toward Abl and decreased along the way to Src. The researchers attribute the changing affinities to conformational shifts in a protein loop that holds Gleevec in place. Although modern Abl and Src differ by 146 amino acids, the team’s analysis pointed to just 15 amino acids that are responsible for Gleevec’s selectivity. Most of them are far from the drug’s binding pocket, which highlights the importance of dynamic changes occurring in a protein far from this site.