title: Identification of a specific inhibitor of the dishevelled PDZ domain.
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 in canonical and noncanonical Wnt 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 Wnt signaling by interrupting the Fz-Dvl interaction.
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Jufang
authors.initials: J
authors.lastname: Shan
authors.forename: De-Li
authors.initials: DL
authors.lastname: Shi
authors.forename: Junmei
authors.initials: J
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D003198:Computer Simulation; D047630:Depsipeptides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000072261:Dishevelled Proteins; D051157:Frizzled Receptors / Q000378:metabolism; D008024:Ligands; D051379:Mice; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D014981:Xenopus; D029867:Xenopus Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606586:DVL1 protein, Xenopus; D047630:Depsipeptides; D000072261:Dishevelled Proteins; D051157:Frizzled Receptors; D008024:Ligands; C534585:NSC 668036; D010750:Phosphoproteins; C555506:WNT3A protein, Xenopus; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D029867:Xenopus Proteins