TY - JOUR
T1 - Structural insight into small molecule action on Frizzleds
AU - Kozielewicz, Paweł
AU - Turku, Ainoleena
AU - Bowin, Carl Fredrik
AU - Petersen, Julian
AU - Valnohova, Jana
AU - Cañizal, Maria Consuelo Alonso
AU - Ono, Yuki
AU - Inoue, Asuka
AU - Hoffmann, Carsten
AU - Schulte, Gunnar
N1 - Funding Information:
We thank Anna Krook for access to the CLARIOstar plate reader and Benoit Vanhol-lebeke for the ΔFZD1–10 HEK293 cells. Joanna J. Sajkowska-Kozielewicz is acknowledged for help in preparing the cartoon schemes. The work was supported by grants from Karolinska Institutet, the Swedish Research Council (2017-04676), the Swedish Cancer Society (CAN2017/561), the Novo Nordisk Foundation (NNF17OC0026940), Stiftelsen Olle Engkvist Byggmästare (2016/193), Wenner-Gren Foundations (UPD2018-0064), Emil and Wera Cornells Stiftelse, and the Marie Curie ITN WntsApp (grant no. 608180; http://www.wntsapp.eu). Computational resources were provided by the Swedish National Infrastructure for Computing (SNIC)–National Supercomputer Centre (NSC) in Linköping and High Performance Computing Centre North (HPC2N) in Umeå.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-019-14149-3
DO - 10.1038/s41467-019-14149-3
M3 - Article
C2 - 31964872
AN - SCOPUS:85078170590
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 414
ER -