Molecular details of receptor activation remain scarce when it comes to Class Frizzled receptors and even less is known about the dynamics between the N-terminal cysteine rich domain (CRD) and the transmembrane domain (TMD) in the absence and presence of ligand. The Class Frizzled comprises 10 isoforms of FZDs (FZD1-10) and Smoothened (SMO), which mediate WNT and Hedgehog signalling respectively. The recently published structure of a full-length SMO bound to the stabilizing compound TC114 builds on emerging concepts from earlier crystal structures of SMO and provides novel insight into how structural rearrangements of the CRD relative to the receptor core coordinate receptor activation while relating this to WNT receptors (1). The ligand-dependent communication between the CRD and the TMD is of special interest because of the known requirement of Class Frizzled receptors to bind endogenous agonists with their CRD. The observed movement of the extracellular extension of SMO-TM6 and extracellular loop 3 suggests a bimodal binding of the agonist to the CRD and the TMD as has been seen for Class B receptors. While this study focuses on the ligand-dependent structural rearrangements on the extracellular part of SMO, it remains unresolved how the conformational changes on the extracellular side of Class Frizzled receptors relate to activating movements of the transmembrane helices on the intracellular side – leaving ample room for future discoveries. The present study opens a new chapter in drug discovery through the use of structure- and mechanism-based drug design to fuel ideas and hopes of successfully targeting FZDs by small molecule drugs. On a more general scale, this work published in Nature Communications by the groups of Fei Xu, Wenfu Tan, Houchao Tao and Raymond Stevens contributes to a better understanding of the role of large extracellular domains in GPCRs with regard to ligand recognition and the engagement of the transmembrane core of the receptor for signal initiation.
 Zhang X et al. (2017). Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand. Nat Commun., 8:15383. [PMID:28513578].