Cryo-EM structure of constitutively active human Frizzled 7 in complex with heterotrimeric Gs

By Lu Xu, Bo Chen, Hannes Schihada, Shane C. Wright, Ainoleena Turku, Yiran Wu, G. Han, Maria Kowalski-Jahn, P. Kozielewicz, Carl-Fredrik Bowin and 5 more. 2021

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Dear Editor, The ten mammalian Frizzleds (FZD 1 – 10 ) belong to the class F of G protein-coupled receptors (GPCRs) and mediate WNT signaling through interaction with transducer proteins including Dishev-elled (DVL) or heterotrimeric G proteins. 1 Their involvement in human disease has put FZDs at the forefront of drug targets, especially anti-cancer therapy. 2 However, no drugs have been developed for ef fi cient pharmacological modulation of FZDs, partially owing to the limited understanding of FZD structure and activation mechanisms. 1,3 Among class F, FZD 7 is intensively pursued due to its relevance in various tumor models, particularly in intestinal cancers. 4 Detailed structures of the receptor complexes would allow for structure-guided discovery of new drug candidates. FZD 1 – 10 share structural similarity with the related class F member Smoothened (SMO), which mediates Hedgehog signaling and is a validated target for cancer therapy. 2 In an effort to understand

Subfields: Cell Biology, Molecular Biology