| Abstract
| - The Wnt signaling pathways are involved in embryo development as well as in tumorigenesis.Dishevelled (Dvl) transduces Wnt signals from the receptor Frizzled (Fz) to downstream components incanonical and noncanonical Wnt signaling pathways. The Dvl PDZ domain is thought to play an essentialrole in both pathways, and we recently demonstrated that the Dvl PDZ domain binds directly to Fz receptors.In this study, using structure-based virtual ligand screening, we identified an organic molecule (NSC668036)from the National Cancer Institute small-molecule library that can bind to the Dvl PDZ domain. We thenused molecular dynamics simulation to analyze the binding between the PDZ domain and NSC668036 indetail. In addition, we showed that, in Xenopus, as expected, NSC668036 inhibited the signaling inducedby Wnt3A. This compound provides a basis for rational design of high-affinity inhibitors of the PDZdomain, which can block Wnt signaling by interrupting the Fz−Dvl interaction.
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