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Structural insight into small molecule action on Frizzleds

Author

Listed:
  • 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
    University Hospital Jena, Friedrich-Schiller University Jena)

  • Yuki Ono

    (Tohoku University)

  • Asuka Inoue

    (Tohoku University)

  • Carsten Hoffmann

    (University of Würzburg
    University Hospital Jena, Friedrich-Schiller University Jena)

  • Gunnar Schulte

    (Karolinska Institutet)

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.

Suggested Citation

  • Paweł Kozielewicz & Ainoleena Turku & Carl-Fredrik Bowin & Julian Petersen & Jana Valnohova & Maria Consuelo Alonso Cañizal & Yuki Ono & Asuka Inoue & Carsten Hoffmann & Gunnar Schulte, 2020. "Structural insight into small molecule action on Frizzleds," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14149-3
    DOI: 10.1038/s41467-019-14149-3
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    Cited by:

    1. Julien Bous & Julia Kinsolving & Lukas Grätz & Magdalena M. Scharf & Jan Hendrik Voss & Berkay Selcuk & Ogün Adebali & Gunnar Schulte, 2024. "Structural basis of frizzled 7 activation and allosteric regulation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Lukas Grätz & Maria Kowalski-Jahn & Magdalena M. Scharf & Pawel Kozielewicz & Michael Jahn & Julien Bous & Nevin A. Lambert & David E. Gloriam & Gunnar Schulte, 2023. "Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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