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. 2009;48(35):6448-52.
doi: 10.1002/anie.200902981.

Sulindac inhibits canonical Wnt signaling by blocking the PDZ domain of the protein Dishevelled

Ho-Jin Lee  1 , Nick X Wang, De-Li Shi, Jie J Zheng
Affiliations

Sulindac inhibits canonical Wnt signaling by blocking the PDZ domain of the protein Dishevelled

Ho-Jin Lee et al. Angew Chem Int Ed Engl. 2009.
No abstract available

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Figures

Figure 1
Figure 1
Sulindac directly binds to the PDZ domain of Dishevelled. (a) the extended 15N-HSQC spectra of 15N-labeled Dvl PDZ domain during the titration of sulindac (blue,free state; red, bound state). (b) Ensemble of the 20 lowest-energy conformations of the PDZ-sulindac complex. Backbone of PDZ domain, magenta; sulindac, blue stick model.
Figure 2
Figure 2
Three-dimensional structure of the Dvl PDZ domain in complex with sulindac. (a) Surface representation showing the binding interface between the Dvl PDZ domain and sulindac (stick model). Hydrophobic amino acid residues in Dvl PDZ are yellow, positively charged residues are blue, negatively charged residues are red, and uncharged polar residues are gray. (b) Sulindac (stick model) and Dvl PDZ (cartoon model). Dvl PDZ domain residues in contact with sulindac are yellow.
Figure 3
Figure 3
Competitive binding experiments. The KD value of the fluorescently labeled, Dapper-derived peptide Rox-DprC was obtained by plotting 1/ΔmP vs 1/ΔS, where ΔmP is the fluorescence polarization change (×1000) of Rox-DprC and ΔS is the concentration change of unlabeled PDZ domain.The KI values of sulindac and sulindac sulfone were obtained by using the equation KDapp = (KD/(1+[I]/KI).
Figure 4
Figure 4
Effect of sulindac on canonical Wnt signaling in Xenopus embryos. (a) Sulindac inhibits canonical Wnt signaling induced by Wnt3A in a concentration-dependent manner. Luciferase activity was measured in ectodermal explants dissected at the late blastula stage. Activity in the untreated control was assigned a value of 100%. Four embryos were treated with 3.5 μg/ml of sulindac; the mean ± SD is shown. The remaining data represent single embryos. (b) Sulindac attenuates canonical Wnt signaling at the level of Dvl. Values are mean luciferase activity ± SD from four independent experiments.
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