Structural and Druggability Landscape of Frizzled G Protein-Coupled Receptors

Class Frizzled G protein-coupled receptors (GPCRs), which includes the Smoothened receptor (SMO) and 10 Frizzled receptors (FZDs), are responsible for mediating fundamental signaling in embryonic development and tissue homeostasis. Dysregulation of these receptors can lead to cancer. Structural understanding of these molecules has provided insight to their function and signaling, and guided drug discovery. To date, the structures of the multi- and individual domains of SMO, 14 FZD extracellular domains, and the transmembrane domain (TMD) of FZD4, have been reported. Here, we review all reported frizzled family structures and diverse signalosome models, with an emphasis on the different ligand binding sites and lipid binding grooves, aiming to uncover the druggability landscape of the frizzled GPCR family.