Structural insight into small molecule action on Frizzleds

• Published in: Nature communications Vol. 11; no. 1; pp. 414 - 16
• Main Authors: Kozielewicz, Paweł, Turku, Ainoleena, Bowin, Carl-Fredrik, Petersen, Julian, Valnohova, Jana, Cañizal, Maria Consuelo Alonso, Ono, Yuki, Inoue, Asuka, Hoffmann, Carsten, Schulte, Gunnar
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 119/118; 14/5; 631/45/612/194; 631/92/436/2387; 82/1; 96/10; 96/33; Agonists; Cell Membrane - metabolism; Dishevelled protein; Dishevelled Proteins - metabolism; Drug delivery; Drug development; Drug Discovery - methods; Drugs; Embryogenesis; Embryonic growth stage; Energy transfer; Frizzled protein; Frizzled Receptors - agonists; Frizzled Receptors - chemistry; Frizzled Receptors - metabolism; HEK293 Cells; Homeostasis; Human pathology; Humanities and Social Sciences; Humans; Ligands; Medicin och hälsovetenskap; Mode of action; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Targeted Therapy - methods; Morpholines - pharmacology; multidisciplinary; Proof of Concept Study; Protein Interaction Domains and Motifs - drug effects; Purines - pharmacology; Pyridines - chemistry; Pyridines - pharmacology; Science; Science (multidisciplinary); Selectivity; Signaling; Smoothened Receptor - agonists; Stem cells; Structure-Activity Relationship; Therapeutic applications; Thiophenes - chemistry; Thiophenes - pharmacology; Wnt protein; Wnt Signaling Pathway - drug effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-14149-3

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 FZD 6 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 FZD 6 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. WNT-Frizzled (FZD) signaling plays a critical role in embryonic development, tissue homeostasis and human disease but no small molecule drugs targeting FZD with distinct efficacy have emerged so far. Here, authors identify the Smoothened agonist SAG1.3 as a partial agonist for FZD6 with limited subtype selectivity.