Molecular mechanism of the arrestin-biased agonism of neurotensin receptor 1 by an intracellular allosteric modulator
文献类型：期刊论文
| 作者 | Sun, Demeng4,5; Li, Xiang5; Yuan, Qingning3; Wang, Yuanxia5; Shi, Pan5; Zhang, Huanhuan5; Wang, Tao5; Sun, Wenjing5; Ling, Shenglong2,5,10; Liu, Yuanchun1 |
| 刊名 | CELL RESEARCH
 |
| 出版日期 | 2025-04-01 |
| 卷号 | 35期号:4页码:284-295 |
| ISSN号 | 1001-0602 |
| DOI | 10.1038/s41422-025-01095-7 |
| 英文摘要 | 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 & Aring;) of NTSR1 in complex with both beta-arrestin1 and the BAM SBI-553. These structures revealed a unique "loop engagement" configuration of beta-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 beta-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. |
| WOS关键词 | CHEMICAL-SYNTHESIS ; COMPLEX ; PHOSPHORYLATION ; IDENTIFICATION |
| 资助项目 | National Natural Science Foundation of China (National Science Foundation of China) ; Hefei KS-V Peptide Biotechnology Co., Ltd.[T2221005] ; Hefei KS-V Peptide Biotechnology Co., Ltd.[22227810] ; Hefei KS-V Peptide Biotechnology Co., Ltd.[22137005] ; Hefei KS-V Peptide Biotechnology Co., Ltd.[T2488301] ; Hefei KS-V Peptide Biotechnology Co., Ltd.[82122067] ; Hefei KS-V Peptide Biotechnology Co., Ltd.[22307113] ; National Natural Science Foundation of China[2022YFC2703105] ; National Natural Science Foundation of China[2021YFA1200104] ; National Key R&D Program of China[2021278] ; Youth Innovation Promotion Association of CAS[2208085J21] ; Science and Technological Fund of Anhui Province for Outstanding Youth ; New Cornerstone Science Foundation[2019B090904008] ; High-level new RD institute[2021B0909050003] ; High-level Innovative Research Institute ; Department of Science and Technology of Guangdong Province ; Sanofi Scholarship Program |
| WOS研究方向 | Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:001449264700001 |
| 出版者 | SPRINGERNATURE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316713]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Yin, Wanchao; Liu, Lei; Xu, H. Eric; Tian, Changlin |
| 作者单位 | 1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Guangdong, Peoples R China 2.Univ Sci & Technol China, Sch Biomed Engn, Suzhou, Jiangsu, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Adv Electron Microscope Ctr, State Key Lab Drug Res, Shanghai, Peoples R China 4.Tsinghua Univ, Tsinghua Peking Ctr Life Sci, Ctr Synthet & Syst Biol, Dept Chem,Minist Educ,Key Lab Bioorgan Phosphorus, Beijing, Peoples R China 5.Univ Sci & Technol China, Joint Ctr Biol Analyt Chem, Div Life Sci & Med, Hefei Natl Lab Phys Sci Microscale, Hefei, Anhui, Peoples R China 6.Shanghai Jiao Tong Univ, Zhangjiang Inst Adv Study, Shanghai, Peoples R China 7.Shanghai Jiao Tong Univ, Sch Chem & Chem Engn, Shanghai, Peoples R China 8.Univ Chinese Acad Sci, Beijing, Peoples R China 9.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou, Guangdong, Peoples R China 10.Univ Sci & Technol China, Suzhou Inst Adv Res, Suzhou, Jiangsu, Peoples R China |
| 推荐引用方式 GB/T 7714 | Sun, Demeng,Li, Xiang,Yuan, Qingning,et al. Molecular mechanism of the arrestin-biased agonism of neurotensin receptor 1 by an intracellular allosteric modulator[J]. CELL RESEARCH,2025,35(4):284-295. |
| APA | Sun, Demeng.,Li, Xiang.,Yuan, Qingning.,Wang, Yuanxia.,Shi, Pan.,...&Tian, Changlin.(2025).Molecular mechanism of the arrestin-biased agonism of neurotensin receptor 1 by an intracellular allosteric modulator.CELL RESEARCH,35(4),284-295. |
| MLA | Sun, Demeng,et al."Molecular mechanism of the arrestin-biased agonism of neurotensin receptor 1 by an intracellular allosteric modulator".CELL RESEARCH 35.4(2025):284-295. |
入库方式： OAI收割
来源：上海药物研究所
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