4DJS

Structure of beta-catenin in complex with a stapled peptide inhibitor

Summary for 4DJS

• Entry DOI: 10.2210/pdb4djs/pdb
• Descriptor: Catenin beta-1, stapled peptide RRWPQ(MK8)ILD(MK8)HVRRVWR (2 entities in total)
• Functional Keywords: transcription regulation, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 58832.40

Authors

Bowman, B.R.,Grossmann, T.N.,Yeh, J.T.-H.,Verdine, G.L. (deposition date: 2012-02-02, release date: 2012-10-17, Last modification date: 2019-07-17)

Primary citation

Grossmann, T.N.,Yeh, J.T.,Bowman, B.R.,Chu, Q.,Moellering, R.E.,Verdine, G.L.
Inhibition of oncogenic Wnt signaling through direct targeting of beta-catenin.
Proc.Natl.Acad.Sci.USA, 109:17942-17947, 2012

PubMed Abstract: Aberrant activation of signaling by the Wnt pathway is strongly implicated in the onset and progression of numerous types of cancer. Owing to the persistent dependence of these tumors on Wnt signaling for growth and survival, inhibition of this pathway is considered an attractive mechanism-based therapeutic approach. Oncogenic activation of Wnt signaling can ensue from a variety of distinct aberrations in the signaling pathway, but most share the common feature of causing increased cellular levels of β-catenin by interfering with its constitutive degradation. β-Catenin serves as a central hub in Wnt signaling by engaging in crucial protein-protein interactions with both negative and positive effectors of the pathway. Direct interference with these protein-protein interactions is a biologically compelling approach toward suppression of β-catenin hyperactivity, but such interactions have proven intransigent with respect to small-molecule targeting. Hence β-catenin remains an elusive target for translational cancer therapy. Here we report the discovery of a hydrocarbon-stapled peptide that directly targets β-catenin and interferes with its ability to serve as a transcriptional coactivator for T-cell factor (TCF) proteins, the downstream transcriptional regulators of the Wnt pathway.

PubMed: 23071338
DOI: 10.1073/pnas.1208396109

Experimental method

X-RAY DIFFRACTION (3.029 Å)