Class B1 GPCRs: insights into multireceptor pharmacology for the treatment of metabolic disease.

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Panjamaporn Sangwung, Joseph D Ho, Tessa Siddall, Jerry Lin, Alejandra Tomas, Ben Jones, Kyle W Sloop
{"title":"Class B1 GPCRs: insights into multireceptor pharmacology for the treatment of metabolic disease.","authors":"Panjamaporn Sangwung, Joseph D Ho, Tessa Siddall, Jerry Lin, Alejandra Tomas, Ben Jones, Kyle W Sloop","doi":"10.1152/ajpendo.00371.2023","DOIUrl":null,"url":null,"abstract":"<p><p>The secretin-like, class B1 subfamily of seven transmembrane-spanning G protein-coupled receptors (GPCRs) consists of 15 members that coordinate important physiological processes. These receptors bind peptide ligands and use a distinct mechanism of activation that is driven by evolutionarily conserved structural features. For the class B1 receptors, the C-terminus of the cognate ligand is initially recognized by the receptor via an N-terminal extracellular domain that forms a hydrophobic ligand-binding groove. This binding enables the N-terminus of the ligand to engage deep into a large volume, open transmembrane pocket of the receptor. Importantly, the phylogenetic basis of this ligand-receptor activation mechanism has provided opportunities to engineer analogs of several class B1 ligands for therapeutic use. Among the most accepted of these are drugs targeting the glucagon-like peptide-1 (GLP-1) receptor for the treatment of type 2 diabetes and obesity. Recently, multifunctional agonists possessing activity at the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as tirzepatide, and others that also contain glucagon receptor activity, have been developed. In this article, we review members of the class B1 GPCR family with focus on receptors for GLP-1, GIP, and glucagon, including their signal transduction and receptor trafficking characteristics. The metabolic importance of these receptors is also highlighted, along with the benefit of polypharmacologic ligands. Furthermore, key structural features and comparative analyses of high-resolution cryogenic electron microscopy structures for these receptors in active-state complexes with either native ligands or multifunctional agonists are provided, supporting the pharmacological basis of such therapeutic agents.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":null,"pages":null},"PeriodicalIF":4.2000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. Endocrinology and metabolism","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1152/ajpendo.00371.2023","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/10 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0

Abstract

The secretin-like, class B1 subfamily of seven transmembrane-spanning G protein-coupled receptors (GPCRs) consists of 15 members that coordinate important physiological processes. These receptors bind peptide ligands and use a distinct mechanism of activation that is driven by evolutionarily conserved structural features. For the class B1 receptors, the C-terminus of the cognate ligand is initially recognized by the receptor via an N-terminal extracellular domain that forms a hydrophobic ligand-binding groove. This binding enables the N-terminus of the ligand to engage deep into a large volume, open transmembrane pocket of the receptor. Importantly, the phylogenetic basis of this ligand-receptor activation mechanism has provided opportunities to engineer analogs of several class B1 ligands for therapeutic use. Among the most accepted of these are drugs targeting the glucagon-like peptide-1 (GLP-1) receptor for the treatment of type 2 diabetes and obesity. Recently, multifunctional agonists possessing activity at the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as tirzepatide, and others that also contain glucagon receptor activity, have been developed. In this article, we review members of the class B1 GPCR family with focus on receptors for GLP-1, GIP, and glucagon, including their signal transduction and receptor trafficking characteristics. The metabolic importance of these receptors is also highlighted, along with the benefit of polypharmacologic ligands. Furthermore, key structural features and comparative analyses of high-resolution cryogenic electron microscopy structures for these receptors in active-state complexes with either native ligands or multifunctional agonists are provided, supporting the pharmacological basis of such therapeutic agents.

B1 类 GPCR:治疗代谢性疾病的多受体药理学透视。
类胰泌素 B1 亚家族的七个跨膜 G 蛋白偶联受体(GPCRs)由 15 个成员组成,它们协调着重要的生理过程。这些受体与肽配体结合,并利用进化保守的结构特征驱动的独特激活机制。对于 B1 类受体来说,同源配体的 C 端最初是通过一个大的 N 端细胞外结构域被受体识别的,该结构域形成一个疏水配体结合槽。这种结合使配体的 N 端深入到受体的一个大容量、开放的跨膜袋中。重要的是,这种配体-受体激活机制的系统发育基础为设计用于治疗的几种 B1 类配体的类似物提供了机会。其中最成功的是针对胰高血糖素样肽-1(GLP-1)受体的药物,用于治疗 2 型糖尿病和肥胖症。最近,开发出了具有 GLP-1 受体和葡萄糖依赖性胰岛素促性多肽(GIP)受体活性的多功能激动剂,如替泽帕特,以及其他也含有胰高血糖素受体活性的药物。本文回顾了 B1 类 GPCR 家族的成员,重点是 GLP-1、GIP 和胰高血糖素受体,包括它们的信号转导和受体贩运特征。文章还强调了这些受体在新陈代谢方面的重要性,以及多药理配体的益处。此外,还提供了这些受体在活性状态下与本地配体或多功能激动剂复合物的关键结构特征和高分辨率低温电子显微镜结构的比较分析,为此类治疗药物的药理学基础提供了支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
9.80
自引率
0.00%
发文量
98
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Endocrinology and Metabolism publishes original, mechanistic studies on the physiology of endocrine and metabolic systems. Physiological, cellular, and molecular studies in whole animals or humans will be considered. Specific themes include, but are not limited to, mechanisms of hormone and growth factor action; hormonal and nutritional regulation of metabolism, inflammation, microbiome and energy balance; integrative organ cross talk; paracrine and autocrine control of endocrine cells; function and activation of hormone receptors; endocrine or metabolic control of channels, transporters, and membrane function; temporal analysis of hormone secretion and metabolism; and mathematical/kinetic modeling of metabolism. Novel molecular, immunological, or biophysical studies of hormone action are also welcome.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信