8RU3

Crystal structure of beta-catenin in complex with alpha-helical peptide inhibitor

Summary for 8RU3

• Entry DOI: 10.2210/pdb8ru3/pdb
• Descriptor: Catenin beta-1, Axin-1, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: peptidometic inhibitor of catenin beta-1, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 59893.52

Authors

Yeste Vazquez, A.,Klintrot, C.I.R.,Grossmann, T.N.,Hennig, S. (deposition date: 2024-01-30, release date: 2024-09-04, Last modification date: 2024-10-09)

Primary citation

Yeste-Vazquez, A.,Paulussen, F.M.,Wendt, M.,Klintrot, R.,Schulte, C.,Wallraven, K.,van Gijzel, L.,Simeonov, B.,van der Gaag, M.,Gerber, A.,Maric, H.M.,Hennig, S.,Grossmann, T.N.
Structure-Based Design of Bicyclic Helical Peptides That Target the Oncogene beta-Catenin.
Angew.Chem.Int.Ed.Engl., :e202411749-e202411749, 2024

PubMed Abstract: The inhibition of intracellular protein-protein interactions is challenging, in particular, when involved interfaces lack pronounced cavities. The transcriptional co-activator protein and oncogene β‑catenin is a prime example of such a challenging target. Despite extensive targeting efforts, available high-affinity binders comprise only large molecular weight Inhibitors. This hampers the further development of therapeutically useful compounds. Herein, we report the design of a considerably smaller peptidomimetic scaffold derived from the α-helical β‑catenin-binding motif of Axin. Sequence maturation and bicyclization provided a stitched peptide with an unprecedented crosslink architecture. The binding mode and site were confirmed by a crystal structure. Further derivatization yielded a β-catenin inhibitor with single-digit micromolar activity in a cell-based assay. This study sheds a light on how to design helix mimetics with reduced molecular weight thereby improving their biological activity.

PubMed: 39167026
DOI: 10.1002/anie.202411749

Experimental method

X-RAY DIFFRACTION (2.001 Å)