Journal
BIOCHEMISTRY
Volume 44, Issue 47, Pages 15495-15503Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi0512602
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Funding
- NCI NIH HHS [CA21765] Funding Source: Medline
- NIGMS NIH HHS [GM061739] Funding Source: Medline
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The Writ signaling pathways are involved in embryo development as well as in tumorigenesis. Dishevelled (Dvl) transduces Writ signals from the receptor Frizzled (Fz) to downstream components in canonical and noncanonical Writ signaling pathways. The Dvl PDZ domain is thought to play an essential role 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 then used molecular dynamics simulation to analyze the binding between the PDZ domain and NSC668036 in detail. In addition, we showed that, in Xenopus, as expected, NSC668036 inhibited the signaling induced by Wnt3A. This compound provides a basis for rational design of high-affinity inhibitors of the PDZ domain, which can block Writ signaling by interrupting the Fz-Dvl interaction.
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