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Angewandte Chemie (International ed. in English) (1)
BMC Chemical Biology (1)
Bioorganic & medicinal chemistry (1)
Lee, Ho-Jin (2)
Wang, Nick X. (2)
Zheng, Jie (2)
Bao, Ju (1)
Shao, Youming (1)
Shi, De-Li (1)
Shi, Tong (1)
Wang, Nick X (1)
Wu, Dianqing (1)
Zheng, Jie J. (1)
Year of Publication
Identification Of Small Molecule TRABID Deubiquitinase Inhibitors By Computation-Based Virtual Screen
BMC Chemical Biology
Wnt/β-catenin-mediated gene transcription plays important roles in a wide range of biological and pathophysiological processes including tumorigenesis where β-catenin-mediated transcription activity frequently elevates. TRABID, a deubiquitinase, was shown to have a positive Wnt/β-catenin-mediated gene transcription and hence holds a promise as a putative anti-cancer target.
In this study, we used a combination of structure based virtual screening and an in vitro deubiquitinase (DUB) assay to identify several small molecules that inhibit TRABID DUB activity. However, these inhibitors failed to show inhibitory effects on β-catenin-mediated gene transcription. In addition, expression of TRABID shRNAs, wildtype TRABID, or the DUB activity-deficient mutant showed little effects on β-catenin-mediated gene transcription.
TRABID may not be a critical component in canonical Wnt/β-catenin signal transduction or that a minute amount of this protein is sufficient for its role in regulating Wnt activity.
Sulindac Inhibits Canonical Wnt Signaling by Blocking the PDZ Domain of Dishevelled
Zheng, Jie J.
Angewandte Chemie (International ed. in English)
Identification of Tripeptides Recognized by the PDZ domain of Dishevelled
Bioorganic & medicinal chemistry
The development of inhibitors of Dishevelled (Dvl) PDZ protein-protein interactions attracts attention due to a possible application in drug discovery and development. Using nuclear magnetic resonance (NMR) spectroscopy, we found that a tripeptide VVV binds to the PDZ domain of Dvl, which is a key component involved in Wnt signaling. Using a computational approach calculating the binding free energy of the complexes of the Dvl PDZ domain and each of the tripeptides VXV (X: any amino acid residue except Pro), we found that a tripeptide VWV had the highest binding affinity. Consistent with the computational result, experimental results showed that the binding of the tripeptide VWV to the Dvl PDZ domain was stronger than that of the tripeptide VVV. The binding affinity of the tripeptide VWV was comparable to that of the organic molecule NSC668036, which was the first identified Dvl PDZ inhibitor. The three-dimensional structure of the complex Dvl1 PDZ/VWV was determined to investigate the role of the energetically favorable W(−1) residue in binding. These interactions were also explored by using molecular dynamic simulation and the molecular mechanics Poisson-Boltzmann surface area method. Taken together, these two tripeptides may be used as modulators of Wnt signaling or as a scaffold to optimize an antagonist for targeting Dvl1 PDZ protein-protein interaction.
binding free energy; protein-ligand interaction; ligand computational screening; NMR; fluorescence spectroscopy
Results 1-3 (3)
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