8RU3

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

8RU3 の概要

• エントリーDOI: 10.2210/pdb8ru3/pdb
• 分子名称: Catenin beta-1, Axin-1, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: peptidometic inhibitor of catenin beta-1, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 59893.52

構造登録者

Yeste Vazquez, A.,Klintrot, C.I.R.,Grossmann, T.N.,Hennig, S. (登録日: 2024-01-30, 公開日: 2024-09-04, 最終更新日: 2024-11-20)

主引用文献

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

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 light on how to design helix mimetics with reduced molecular weight thereby improving their biological activity.

PubMed: 39167026
DOI: 10.1002/anie.202411749

実験手法

X-RAY DIFFRACTION (2.001 Å)