Molecular mechanism of the arrestin-biased agonism of neurotensin receptor 1 by an intracellular allosteric modulator

IF 25.9 1区 生物学 Q1 CELL BIOLOGY
Demeng Sun, Xiang Li, Qingning Yuan, Yuanxia Wang, Pan Shi, Huanhuan Zhang, Tao Wang, Wenjing Sun, Shenglong Ling, Yuanchun Liu, Jinglin Lai, Wenqin Xie, Wanchao Yin, Lei Liu, H. Eric Xu, Changlin Tian
{"title":"Molecular mechanism of the arrestin-biased agonism of neurotensin receptor 1 by an intracellular allosteric modulator","authors":"Demeng Sun, Xiang Li, Qingning Yuan, Yuanxia Wang, Pan Shi, Huanhuan Zhang, Tao Wang, Wenjing Sun, Shenglong Ling, Yuanchun Liu, Jinglin Lai, Wenqin Xie, Wanchao Yin, Lei Liu, H. Eric Xu, Changlin Tian","doi":"10.1038/s41422-025-01095-7","DOIUrl":null,"url":null,"abstract":"Biased allosteric modulators (BAMs) of G protein-coupled receptors (GPCRs) have been at the forefront of drug discovery owing to their potential to selectively stimulate therapeutically relevant signaling and avoid on-target side effects. Although structures of GPCRs in complex with G protein or GRK in a BAM-bound state have recently been resolved, revealing that BAM can induce biased signaling by directly modulating interactions between GPCRs and these two transducers, no BAM-bound GPCR–arrestin complex structure has yet been determined, limiting our understanding of the full pharmacological profile of BAMs. Herein, we developed a chemical protein synthesis strategy to generate neurotensin receptor 1 (NTSR1) with defined hexa-phosphorylation at its C-terminus and resolved high-resolution cryo-EM structures (2.65–2.88 Å) of NTSR1 in complex with both β-arrestin1 and the BAM SBI-553. These structures revealed a unique “loop engagement” configuration of β-arrestin1 coupling to NTSR1 in the presence of SBI-553, markedly different from the typical “core engagement” configuration observed in the absence of BAMs. This configuration is characterized by the engagement of the intracellular loop 3 of NTSR1 with a cavity in the central crest of β-arrestin1, representing a previously unobserved, arrestin-selective conformation of GPCR. Our findings fill the critical knowledge gap regarding the regulation of GPCR–arrestin interactions and biased signaling by BAMs, which would advance the development of safer and more efficacious GPCR-targeted therapeutics.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 4","pages":"284-295"},"PeriodicalIF":25.9000,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-025-01095-7.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Research","FirstCategoryId":"99","ListUrlMain":"https://www.nature.com/articles/s41422-025-01095-7","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Biased allosteric modulators (BAMs) of G protein-coupled receptors (GPCRs) have been at the forefront of drug discovery owing to their potential to selectively stimulate therapeutically relevant signaling and avoid on-target side effects. Although structures of GPCRs in complex with G protein or GRK in a BAM-bound state have recently been resolved, revealing that BAM can induce biased signaling by directly modulating interactions between GPCRs and these two transducers, no BAM-bound GPCR–arrestin complex structure has yet been determined, limiting our understanding of the full pharmacological profile of BAMs. Herein, we developed a chemical protein synthesis strategy to generate neurotensin receptor 1 (NTSR1) with defined hexa-phosphorylation at its C-terminus and resolved high-resolution cryo-EM structures (2.65–2.88 Å) of NTSR1 in complex with both β-arrestin1 and the BAM SBI-553. These structures revealed a unique “loop engagement” configuration of β-arrestin1 coupling to NTSR1 in the presence of SBI-553, markedly different from the typical “core engagement” configuration observed in the absence of BAMs. This configuration is characterized by the engagement of the intracellular loop 3 of NTSR1 with a cavity in the central crest of β-arrestin1, representing a previously unobserved, arrestin-selective conformation of GPCR. Our findings fill the critical knowledge gap regarding the regulation of GPCR–arrestin interactions and biased signaling by BAMs, which would advance the development of safer and more efficacious GPCR-targeted therapeutics.

Abstract Image

Abstract Image

一种细胞内异位调节剂对神经紧张素受体 1 的抑制作用的分子机制
G蛋白偶联受体(gpcr)的偏化变抗调节剂(BAMs)由于具有选择性刺激治疗相关信号和避免靶侧副作用的潜力,一直处于药物发现的前沿。虽然gpcr与G蛋白或GRK结合状态的复合物结构最近已经被解决,揭示了BAM可以通过直接调节gpcr与这两种转导器之间的相互作用来诱导偏导信号,但尚未确定bam结合的gpcr -阻滞复合物结构,限制了我们对BAMs完整药理学特征的理解。在此,我们开发了一种化学蛋白质合成策略来生成神经紧张素受体1 (NTSR1),其c端具有明确的六磷酸,并且NTSR1与β-arrestin1和BAM SBI-553复合物具有高分辨率的冷冻电镜结构(2.65-2.88 Å)。这些结构揭示了在SBI-553存在时β-arrestin1与NTSR1耦合的独特“环接合”构型,明显不同于在没有BAMs存在时观察到的典型“核心接合”构型。这种结构的特点是NTSR1的胞内环3与β-arrestin1的中央嵴的空腔结合,代表了以前未观察到的GPCR的逮捕选择性构象。我们的发现填补了关于调控gpcr -抑制蛋白相互作用和BAMs偏倚信号传导的关键知识空白,这将推动更安全、更有效的gpcr靶向治疗的发展。
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
Cell Research
Cell Research 生物-细胞生物学
CiteScore
53.90
自引率
0.70%
发文量
2420
审稿时长
2.3 months
期刊介绍: Cell Research (CR) is an international journal published by Springer Nature in partnership with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). It focuses on publishing original research articles and reviews in various areas of life sciences, particularly those related to molecular and cell biology. The journal covers a broad range of topics including cell growth, differentiation, and apoptosis; signal transduction; stem cell biology and development; chromatin, epigenetics, and transcription; RNA biology; structural and molecular biology; cancer biology and metabolism; immunity and molecular pathogenesis; molecular and cellular neuroscience; plant molecular and cell biology; and omics, system biology, and synthetic biology. CR is recognized as China's best international journal in life sciences and is part of Springer Nature's prestigious family of Molecular Cell Biology journals.
×
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:604180095
Book学术官方微信