Structural insight into Class F receptors – What have we learnt regarding agonist‐induced activation?

Abstract Class F receptors, including the ten Frizzleds (FZD 1‐10 ) and SMO, mediate the effects of WNTs and hedgehog proteins and belong to the superfamily of G protein‐coupled receptors (GPCRs). While the recent, high‐resolution insight into mechanisms of GPCR activation provides a better understanding of receptor activation in Class A, B and C GPCRs, it remains unclear how Class F receptors bind their ligands, how ligand binding is translated to receptor activation and how signal initiation and specification are achieved. Here, we summarize recent efforts in elucidating Class F receptor structure and activation mechanisms and critically discuss the progress made in this area. A better understanding of the activation mechanisms of Class F receptors is required to engage in mechanism‐based and structure‐guided drug discovery to exploit the large therapeutic potential of targeting these receptors pharmacologically.