7AR4

Crystal structure of beta-catenin in complex with cyclic peptide inhibitor

This is a non-PDB format compatible entry.

Summary for 7AR4

• Entry DOI: 10.2210/pdb7ar4/pdb
• Descriptor: Catenin beta-1, Cadherin-1, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (5 entities in total)
• Functional Keywords: wnt signaling, peptide inhibitor, protein-peptide interaction, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 60401.35

Authors

Wendt, M.,Pearce, N.M.,Grossmann, T.N.,Hennig, S. (deposition date: 2020-10-23, release date: 2021-04-07, Last modification date: 2024-11-20)

Primary citation

Wendt, M.,Bellavita, R.,Gerber, A.,Efrem, N.L.,van Ramshorst, T.,Pearce, N.M.,Davey, P.R.J.,Everard, I.,Vazquez-Chantada, M.,Chiarparin, E.,Grieco, P.,Hennig, S.,Grossmann, T.N.
Bicyclic beta-Sheet Mimetics that Target the Transcriptional Coactivator beta-Catenin and Inhibit Wnt Signaling.
Angew.Chem.Int.Ed.Engl., 60:13937-13944, 2021

PubMed Abstract: Protein complexes are defined by the three-dimensional structure of participating binding partners. Knowledge about these structures can facilitate the design of peptidomimetics which have been applied for example, as inhibitors of protein-protein interactions (PPIs). Even though β-sheets participate widely in PPIs, they have only rarely served as the basis for peptidomimetic PPI inhibitors, in particular when addressing intracellular targets. Here, we present the structure-based design of β-sheet mimetics targeting the intracellular protein β-catenin, a central component of the Wnt signaling pathway. Based on a protein binding partner of β-catenin, a macrocyclic peptide was designed and its crystal structure in complex with β-catenin obtained. Using this structure, we designed a library of bicyclic β-sheet mimetics employing a late-stage diversification strategy. Several mimetics were identified that compete with transcription factor binding to β-catenin and inhibit Wnt signaling in cells. The presented design strategy can support the development of inhibitors for other β-sheet-mediated PPIs.

PubMed: 33783110
DOI: 10.1002/anie.202102082

Experimental method

X-RAY DIFFRACTION (2.6 Å)