The first X-ray crystal structure of a flexible member of an enzyme family involved in diseases ranging from cancer and diabetes to inflammation and asthma could bolster efforts to develop drugs that selectively inhibit the enzymes. Pharmaceutical companies trying to develop drugs aimed at the phosphoinositide-3-OH kinases (PI3Ks) have been stymied by an inability to target specific family members and therefore minimize side effects from interactions with other members. A team led by Roger L. Williams of the Medical Research Council’s Laboratory of Molecular Biology, in Cambridge, England, solved the structure of the δ isoform of PI3K bound to several inhibitors that were flat or shaped like propellers (Nat. Chem. Biol., DOI: 10.1038/nchembio.293). This isoform, associated with inflammation, has a topology similar to other structurally characterized PI3K isoforms, but it appears to be more flexible. For example, the team found that propeller-shaped inhibitors squeeze into a site normally occupied by the energy-giving molecule ATP. In order to fit, the inhibitors create a new cavity in a section of the enzyme that is not normally open. Learning more about the conformational flexibility of enzymes that otherwise look the same could be key to designing drugs specific to a particular isoform, Williams says.