Peptide Disciplines Dishevelled Protein

The protein Dishevelled got its name because mutated versions cause misaligned hairs to grow on fruit flies. It can also make a mess of people's health, because it regulates the Wnt signaling pathway, which is associated with progression of colorectal and other cancers. Rami N. Hannoush, Sachdev S. Sidhu, and coworkers at Genentech report having identified a peptide ligand, pen-N3, that potently inhibits Dishevelled and could therefore lead to anticancer therapeutics (Nat. Chem. Biol. 2009, 5, 217). Other inhibitors of the protein have been found, but pen-N3 binds to Dishevelled's PDZ domain with 10 times greater affinity. Dishevelled has been very difficult to analyze structurally, but the group obtained the first crystal structures of the inhibitor-bound protein, which reveal the mechanism of inhibitory action and could help in the structure-based design of other inhibitors. No Dishevelled inhibitors are currently in clinical trials, Hannoush notes, but pen-N3 inhibits Wnt signaling in cells and appears to be specific and nontoxic, suggesting it could lead to anticancer drugs.