International Union of Basic and Clinical Pharmacology CXV: The Class F of G Protein-Coupled Receptors.

IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY
Gunnar Schulte
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引用次数: 0

Abstract

The class F of G protein-coupled receptors (GPCRs) consists of 10 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. 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 the 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.

国际基础与临床药理学联合会。CXV:G 蛋白偶联受体 F 类。
F 类 G 蛋白偶联受体(GPCR)由十个 Frizzleds(FZD1-10)和 Smoothened(SMO)组成。FZDs与Wingless/Int-1(WNT)家族分泌的脂糖蛋白结合并被激活,SMO则被作用于跨膜蛋白Patched(PTCH)的形态发生因子Hedgehog(Hh)家族间接激活。自第一份 F 类 GPCR IUPHAR 命名报告发布以来的 14 年间,我们对 FZDs 和 SMO 作为动态跨膜受体和分子机器的认识不断进步,因此有必要对其进行更新。本文重点介绍分子药理学和结构生物学方面的进展,这些进展为配体识别、受体激活机制、信号启动和信号规范提供了新的机制认识。此外,F 类 GPCR 继续发展成为药物靶点,基因编码生物传感器和 CRISP/Cas9 编辑细胞系统等新技术和工具也有助于对这些受体进行精细的功能分析。此外,晶体结构分析和低温电子显微镜技术的进步也促进了我们对结构-功能关系知识的快速发展,为药物开发提供了一个很好的起点。尽管取得了这些进展,但要全面了解 WNT/FZD 和 Hh/SMO 信号系统的复杂性,仍然存在问题和挑战。意义声明 近年来的研究从功能和结构上深入了解了 Frizzleds 和 Smoothened 的激活机制。这些进展进一步加深了我们对配体识别、受体激活、信号规范和启动的机理认识,同时也带来了更广泛的机遇,使我们能够利用生物制剂和小分子化合物,针对 F 类 GPCRs 进行治疗和再生医学研究。
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来源期刊
Pharmacological Reviews
Pharmacological Reviews 医学-药学
CiteScore
34.70
自引率
0.50%
发文量
40
期刊介绍: Pharmacological Reviews is a highly popular and well-received journal that has a long and rich history of success. It was first published in 1949 and is currently published bimonthly online by the American Society for Pharmacology and Experimental Therapeutics. The journal is indexed or abstracted by various databases, including Biological Abstracts, BIOSIS Previews Database, Biosciences Information Service, Current Contents/Life Sciences, EMBASE/Excerpta Medica, Index Medicus, Index to Scientific Reviews, Medical Documentation Service, Reference Update, Research Alerts, Science Citation Index, and SciSearch. Pharmacological Reviews offers comprehensive reviews of new pharmacological fields and is able to stay up-to-date with published content. Overall, it is highly regarded by scholars.
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