Identification of a specific inhibitor of the Dishevelled PDZ domain

Jufang Shan, De Li Shi, Junmei Wang, Jie Zheng

Research output: Contribution to journalArticle

144 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)15495-15503
Number of pages9
JournalBiochemistry
Volume44
Issue number47
DOIs
StatePublished - Nov 29 2005

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PDZ Domains
Frizzled Receptors
Wnt Signaling Pathway
Wnt Receptors
Molecules
Small Molecule Libraries
National Cancer Institute (U.S.)
Molecular dynamics
Molecular Dynamics Simulation
Screening
Xenopus
Embryonic Development
Ligands
Carcinogenesis
Computer simulation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Identification of a specific inhibitor of the Dishevelled PDZ domain. / Shan, Jufang; Shi, De Li; Wang, Junmei; Zheng, Jie.

In: Biochemistry, Vol. 44, No. 47, 29.11.2005, p. 15495-15503.

Research output: Contribution to journalArticle

Shan, Jufang ; Shi, De Li ; Wang, Junmei ; Zheng, Jie. / Identification of a specific inhibitor of the Dishevelled PDZ domain. In: Biochemistry. 2005 ; Vol. 44, No. 47. pp. 15495-15503.
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