Structural insight into small molecule action on Frizzleds.
Paweł Kozielewicz1, Ainoleena Turku1, Carl-Fredrik Bowin1
1Section of Receptor Biology & Signaling, Department of Physiology & Pharmacology, Karolinska Institutet, S-17165, Stockholm, Sweden.
Nature Communications
|January 23, 2020
Summary
Researchers identified SAG1.3, a small molecule, as a partial agonist of Frizzled 6 (FZD6). This discovery offers a new starting point for developing targeted therapies for diseases linked to FZD signaling pathways.
Area of Science:
- Molecular biology
- Pharmacology
- Biochemistry
Background:
- WNT-Frizzled (FZD) signaling is crucial for development and homeostasis.
- FZD receptors are implicated in human diseases, making them therapeutic targets.
- Existing small molecule drugs targeting FZDs lack distinct efficacy.
Purpose of the Study:
- To identify small molecules targeting Frizzled receptors.
- To characterize the mechanism of action of SAG1.3 on FZD6.
- To establish FZDs as druggable targets via their transmembrane core.
Main Methods:
- In silico analysis
- Resonance energy transfer (RET) assays
- Luciferase-based assays
- Biochemical assays to study receptor-ligand interactions
Main Results:
- SAG1.3 identified as a partial agonist of Frizzled 6 (FZD6).
- SAG1.3 binds to FZD6, inducing conformational changes.
- SAG1.3 modulates G protein recruitment and FZD-Dishevelled interactions.
Conclusions:
- Frizzled receptors are targetable by small molecules acting on their seven-transmembrane domain.
- SAG1.3 provides a foundation for structure-guided drug discovery for FZD-related pathologies.
- This work opens avenues for developing novel therapeutics exploiting FZD signaling.
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