Structural insight into small molecule action on Frizzleds

Paweł Kozielewicz, Ainoleena Turku, Carl-Fredrik Bowin, Julian Petersen, Jana Valnohova, Maria Consuelo Alonso Cañizal, Yuki Ono, Asuka Inoue, Carsten Hoffmann and Gunnar Schulte ()
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Paweł Kozielewicz: Karolinska Institutet
Ainoleena Turku: Karolinska Institutet
Carl-Fredrik Bowin: Karolinska Institutet
Julian Petersen: Karolinska Institutet
Jana Valnohova: Karolinska Institutet
Maria Consuelo Alonso Cañizal: University of Würzburg
Yuki Ono: Tohoku University
Asuka Inoue: Tohoku University
Carsten Hoffmann: University of Würzburg
Gunnar Schulte: Karolinska Institutet

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14149-3

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DOI: 10.1038/s41467-019-14149-3

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