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8RU4

Crystal structure of Human Catenin Beta-1 in complex with stitched peptide inhibitor

Summary for 8RU4
Entry DOI10.2210/pdb8ru4/pdb
DescriptorCatenin beta-1, Axin-1, alpha-D-glucopyranose, ... (7 entities in total)
Functional Keywordspeptidometic inhibitor of catenin beta-1, signaling protein
Biological sourceHomo sapiens (human)
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Total number of polymer chains3
Total formula weight117296.04
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: 2024-11-20)
Primary citationYeste-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., 63:e202411749-e202411749, 2024
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.13 Å)
Structure validation

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