8G4Y

Structure of ZNRF3 ECD bound to peptide MK1-3.6.10

Summary for 8G4Y

• Entry DOI: 10.2210/pdb8g4y/pdb
• Descriptor: E3 ubiquitin-protein ligase ZNRF3, MK1-3.6.10 (3 entities in total)
• Functional Keywords: ubiquitin ligase, wnt signal, cell surface, ckp, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 24162.19

Authors

Harris, S.F.,Wu, P. (deposition date: 2023-02-10, release date: 2023-12-20, Last modification date: 2024-10-23)

Primary citation

Kschonsak, Y.T.,Gao, X.,Miller, S.E.,Hwang, S.,Marei, H.,Wu, P.,Li, Y.,Ruiz, K.,Dorighi, K.,Holokai, L.,Perampalam, P.,Tsai, W.K.,Kee, Y.S.,Agard, N.J.,Harris, S.F.,Hannoush, R.N.,de Sousa E Melo, F.
Potent and selective binders of the E3 ubiquitin ligase ZNRF3 stimulate Wnt signaling and intestinal organoid growth.
Cell Chem Biol, 31:1176-, 2024

PubMed Abstract: Selective and precise activation of signaling transduction cascades is key for cellular reprogramming and tissue regeneration. However, the development of small- or large-molecule agonists for many signaling pathways has remained elusive and is rate limiting to realize the full clinical potential of regenerative medicine. Focusing on the Wnt pathway, here we describe a series of disulfide-constrained peptides (DCPs) that promote Wnt signaling activity by modulating the cell surface levels of ZNRF3, an E3 ubiquitin ligase that controls the abundance of the Wnt receptor complex FZD/LRP at the plasma membrane. Mechanistically, monomeric DCPs induce ZNRF3 ubiquitination, leading to its cell surface clearance, ultimately resulting in FZD stabilization. Furthermore, we engineered multimeric DCPs that induce expansive growth of human intestinal organoids, revealing a dependence between valency and ZNRF3 clearance. Our work highlights a strategy for the development of potent, biologically active Wnt signaling pathway agonists via targeting of ZNRF3.

PubMed: 38056465
DOI: 10.1016/j.chembiol.2023.11.006

Experimental method

X-RAY DIFFRACTION (1.41 Å)