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Nat Commun. 2020 Jan 21;11(1):414. doi: 10.1038/s41467-019-14149-3.

Structural insight into small molecule action on Frizzleds.

Author information

1
Section of Receptor Biology & Signaling, Department of Physiology & Pharmacology, Karolinska Institutet, S-17165, Stockholm, Sweden.
2
Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Str. 9, 97078, Würzburg, Germany.
3
Institute for Molecular Cell Biology, CMB-Center for Molecular Biomedicine, University Hospital Jena, Friedrich-Schiller University Jena, Hans-Knöll-Strasse 2, 07745, Jena, Germany.
4
Department of Pharmacological Sciences, Tohoku University, Sendai, 980-8578, Japan.
5
Section of Receptor Biology & Signaling, Department of Physiology & Pharmacology, Karolinska Institutet, S-17165, Stockholm, Sweden. gunnar.schulte@ki.se.

Abstract

WNT-Frizzled (FZD) signaling plays a critical role in embryonic development, stem cell regulation and tissue homeostasis. FZDs are linked to severe human pathology and are seen as a promising target for therapy. Despite intense efforts, no small molecule drugs with distinct efficacy have emerged. Here, we identify the Smoothened agonist SAG1.3 as a partial agonist of FZD6 with limited subtype selectivity. Employing extensive in silico analysis, resonance energy transfer- and luciferase-based assays we describe the mode of action of SAG1.3. We define the ability of SAG1.3 to bind to FZD6 and to induce conformational changes in the receptor, recruitment and activation of G proteins and dynamics in FZD-Dishevelled interaction. Our results provide the proof-of-principle that FZDs are targetable by small molecules acting on their seven transmembrane spanning core. Thus, we provide a starting point for a structure-guided and mechanism-based drug discovery process to exploit the potential of FZDs as therapeutic targets.

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