3SL9

X-ray structure of Beta catenin in complex with Bcl9

Summary for 3SL9

• Entry DOI: 10.2210/pdb3sl9/pdb
• Related: 2GL7 3SLA
• Descriptor: Catenin beta-1, B-cell CLL/lymphoma 9 protein, 1,2-ETHANEDIOL, ... (7 entities in total)
• Functional Keywords: armadillo repeat, components of the wnt signaling pathway, beta catenin, signaling protein, protein binding
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P35222; Nucleus (By similarity): O00512
• Total number of polymer chains: 8
• Total formula weight: 99549.13

Authors

Gupta, D.,Bienz, M. (deposition date: 2011-06-24, release date: 2012-02-29, Last modification date: 2023-09-13)

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 (2.2 Å)