Abstract：
The class F of G protein-coupled receptors (GPCRs) consists of ten Frizzleds (FZD1-10) and Smoothened (SMO). FZDs bind and are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family and SMO is indirectly activated by the Hedgehog (Hh) family of morphogens acting on the transmembrane protein Patched (PTCH). The advance of our understanding of FZDs and SMO as dynamic transmembrane receptors and molecular machines, which emerged during the past 14 years since the first class F GPCR IUPHAR nomenclature report, justifies an update. This article focuses on the advances in molecular pharmacology and structural biology providing new mechanistic insight into ligand recognition, receptor activation mechanisms, signal initiation and signal specification. Furthermore, class F GPCRs continue to develop as drug targets, and novel technologies and tools such as genetically encoded biosensors and CRISP/Cas9 edited cell systems have contributed to refined functional analysis of these receptors. Also, advances in crystal structure analysis and cryogenic electron microscopy contribute to a rapid development of our knowledge about structure-function relationships providing a great starting point for drug development. Despite the progress questions and challenges remain to fully understand the complexity of the WNT/FZD and Hh/SMO signaling systems. Significance Statement The recent years of research have brought about substantial functional and structural insight into mechanisms of activation of Frizzleds and Smoothened. While the advance furthers our mechanistic understanding of ligand recognition, receptor activation, signal specification and initiation, broader opportunities emerge that allow targeting class F GPCRs for therapy and regenerative medicine employing both biologics and small molecule compounds.
摘要：
G蛋白偶联受体（GPCR）的F类由10个卷曲蛋白（FZD1-10）和平滑蛋白（SMO）组成。FZD结合无翼/Int-1（WNT）家族的分泌的脂糖蛋白并被其激活，而SMO则被Hedgehog（Hh）家族的形态发生素作用于跨膜蛋白Patched（PTCH）间接激活。我们对FZD和SMO作为动态跨膜受体和分子机器的理解的进展，自第一份F类GPCRIUPHAR命名报告以来的过去14年中出现的，对更新进行校正。本文重点介绍了分子药理学和结构生物学的进展，为配体识别提供了新的机制见解，受体激活机制，信号启动和信号规范。此外，F类GPCRs继续发展为药物靶标，基因编码的生物传感器和CRISP/Cas9编辑的细胞系统等新技术和工具为这些受体的精细功能分析做出了贡献。此外，晶体结构分析和低温电子显微镜的进步有助于我们对结构-功能关系的知识的快速发展，为药物开发提供了一个很好的起点。尽管取得了进展，但在充分理解WNT/FZD和Hh/SMO信号系统的复杂性方面仍然存在问题和挑战。重要性陈述近年来的研究带来了对卷曲和平滑的激活机制的实质性功能和结构见解。虽然这一进展进一步加深了我们对配体识别的机械理解，受体激活,信号规格和启动，出现了更广泛的机会，允许靶向F类GPCRs用于使用生物制剂和小分子化合物的治疗和再生医学。
