3SLA

X-ray structure of first four repeats of human beta-catenin

Summary for 3SLA

• Entry DOI: 10.2210/pdb3sla/pdb
• Related: 2GL7 3SL9
• Descriptor: Catenin beta-1, GLYCEROL, SODIUM ION, ... (4 entities in total)
• Functional Keywords: beta catenin, armadillo repeat, key component of the wnt signaling pathway, signaling protein
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P35222
• Total number of polymer chains: 5
• Total formula weight: 92479.47

Authors

Gupta, D.,Bienz, M. (deposition date: 2011-06-24, release date: 2012-02-29, Last modification date: 2024-02-28)

Primary citation

de la Roche, M.,Rutherford, T.J.,Gupta, D.,Veprintsev, D.B.,Saxty, B.,Freund, S.M.,Bienz, M.
An intrinsically labile alpha-helix abutting the BCL9-binding site of beta-catenin is required for its inhibition by carnosic acid.
Nat Commun, 3:680-680, 2012

PubMed Abstract: Wnt/β-catenin signalling controls development and tissue homeostasis. Moreover, activated β-catenin can be oncogenic and, notably, drives colorectal cancer. Inhibiting oncogenic β-catenin has proven a formidable challenge. Here we design a screen for small-molecule inhibitors of β-catenin's binding to its cofactor BCL9, and discover five related natural compounds, including carnosic acid from rosemary, which attenuates transcriptional β-catenin outputs in colorectal cancer cells. Evidence from NMR and analytical ultracentrifugation demonstrates that the carnosic acid response requires an intrinsically labile α-helix (H1) amino-terminally abutting the BCL9-binding site in β-catenin. Similarly, in colorectal cancer cells with hyperactive β-catenin signalling, carnosic acid targets predominantly the transcriptionally active ('oncogenic') form of β-catenin for proteasomal degradation in an H1-dependent manner. Hence, H1 is an 'Achilles' Heel' of β-catenin, which can be exploited for destabilization of oncogenic β-catenin by small molecules, providing proof-of-principle for a new strategy for developing direct inhibitors of oncogenic β-catenin.

PubMed: 22353711
DOI: 10.1038/ncomms1680

Experimental method

X-RAY DIFFRACTION (2.5 Å)