5WBS

Crystal structure of Frizzled-7 CRD with an inhibitor peptide Fz7-21

Summary for 5WBS

• Entry DOI: 10.2210/pdb5wbs/pdb
• Descriptor: Frizzled-7,inhibitor peptide Fz7-21 (2 entities in total)
• Functional Keywords: frizzled, wnt signaling, inhibitor, dimerization, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 160842.31

Authors

Nile, A.H.,Mukund, S.,Hannoush, R.N.,Wang, W. (deposition date: 2017-06-29, release date: 2018-04-18, Last modification date: 2024-10-30)

Primary citation

Nile, A.H.,de Sousa E Melo, F.,Mukund, S.,Piskol, R.,Hansen, S.,Zhou, L.,Zhang, Y.,Fu, Y.,Gogol, E.B.,Komuves, L.G.,Modrusan, Z.,Angers, S.,Franke, Y.,Koth, C.,Fairbrother, W.J.,Wang, W.,de Sauvage, F.J.,Hannoush, R.N.
A selective peptide inhibitor of Frizzled 7 receptors disrupts intestinal stem cells.
Nat. Chem. Biol., 14:582-590, 2018

PubMed Abstract: Regeneration of the adult intestinal epithelium is mediated by a pool of cycling stem cells, which are located at the base of the crypt, that express leucine-rich-repeat-containing G-protein-coupled receptor 5 (LGR5). The Frizzled (FZD) 7 receptor (FZD7) is enriched in LGR5 intestinal stem cells and plays a critical role in their self-renewal. Yet, drug discovery approaches and structural bases for targeting specific FZD isoforms remain poorly defined. FZD proteins interact with Wnt signaling proteins via, in part, a lipid-binding groove on the extracellular cysteine-rich domain (CRD) of the FZD receptor. Here we report the identification of a potent peptide that selectively binds to the FZD7 CRD at a previously uncharacterized site and alters the conformation of the CRD and the architecture of its lipid-binding groove. Treatment with the FZD7-binding peptide impaired Wnt signaling in cultured cells and stem cell function in intestinal organoids. Together, our data illustrate that targeting the lipid-binding groove holds promise as an approach for achieving isoform-selective FZD receptor inhibition.

PubMed: 29632413
DOI: 10.1038/s41589-018-0035-2

Experimental method

X-RAY DIFFRACTION (2.88 Å)