8RU4
Crystal structure of Human Catenin Beta-1 in complex with stitched peptide inhibitor
Summary for 8RU4
| Entry DOI | 10.2210/pdb8ru4/pdb |
| Descriptor | Catenin beta-1, Axin-1, alpha-D-glucopyranose, ... (7 entities in total) |
| Functional Keywords | peptidometic inhibitor of catenin beta-1, signaling protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 117296.04 |
| 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 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., 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: 39167026DOI: 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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