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  2. 上海药物研究所
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  5. 原创新药研究全国重点实验室
Cryo-EM structure of the full-length LGR4-RSPOs complex and a targeting nanobody for anti-obesity therapy

文献类型：期刊论文

作者Zhang, Zhongyun2,3; Wang, Lu1; Qiao, Huarui1,4,5; Jiang, Haowen1; Guo, Shaojue1; Li, Yuying1; Zhang, Ningning2,3; Geng, Tengjie1; Cui, Qianqian1; Lan, Zhongyun1
刊名NATURE COMMUNICATIONS
出版日期2025-09-25
卷号16期号:1页码:17
DOI10.1038/s41467-025-63410-5
英文摘要Obesity poses a substantial threat to human health but lacks effective management. Recent advancements in large-scale deep sequencing and cryo-electron microscopy (cryo-EM) have transformed drug discovery paradigms. Leveraging prior genetics investigation, we pinpointed Leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) as a promising target for combating obesity. Here, we present cryo-EM structures of full-length LGR4 alone and in complex with RSPO2(FU). Notably, we develop an inhibitory nanobody (NB21) that blocks the binding of RSPO1/2 to LGR4, and we also determine the structure of the LGR4-NB21 complex. NB21-mFc (NB21 fused with mouse IgG2) effectively inhibits the canonical Wnt signaling pathway, thereby enhancing mitochondrial respiration and thermogenesis in beige adipocytes. In vivo, NB21-mFc increases energy expenditure by promoting the browning of white fat, conferring resistance to both diet-induced and genetic (ob/ob) obesity. Furthermore, LGR4 deficiency abolishes the effects of NB21-mFc in boosting the browning program and subsequent weight reduction. In summary, our study unveils structural insights into the LGR4-RSPOs and LGR4-NB21 complexes, paving the way for the development of an LGR4-targeting nanobody for weight loss.
WOS关键词CRYSTAL-STRUCTURE ; WNT/BETA-CATENIN ; DRUG DEVELOPMENT ; LGR4 ; OVERWEIGHT ; OBESITY ; RECEPTORS ; RECOGNITION ; DISCOVERY ; INCRETIN
资助项目National Natural Science Foundation of China[U24A20675] ; National Natural Science Foundation of China[92457302] ; National Natural Science Foundation of China[81930021] ; National Natural Science Foundation of China[82370845] ; National Natural Science Foundation of China[82130099] ; National Natural Science Foundation of China[8247031318] ; National Natural Science Foundation of China[82273983] ; National Key Research and Development Program of China[2022YFC2505201] ; Natural Science Major Program of Shanghai Municipal Education Commission[2023ZKZD22] ; Science and Technology Commission of Shanghai Municipality[18JC1415400] ; Science and Technology Commission of Shanghai Municipality[21JC1404400] ; Shanghai Outstanding Academic Leaders Plan[LJ2023078] ; CAS Interdisciplinary Team of Light of West China Program[xbzg-zdsys-202405]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001581146700023
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/321543]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Ning, Guang; Li, Jia; Wang, Jiqiu; Geng, Yong
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
2.Shanghai Jiao Tong Univ, Ruijin Hosp, Shanghai Inst Endocrine & Metab Dis, Dept Endocrine & Metab Dis,Sch Med, Shanghai, Peoples R China
3.Natl Hlth Commiss PR China, Shanghai Natl Clin Res Ctr Metab Dis, Shanghai Natl Ctr Translat Med, Key Lab Endocrine & Metab Dis, Shanghai, Peoples R China
4.Shanghai Tech Univ, Sch Life Sci & Technol, Lingang Lab, Shanghai, Peoples R China
5.Univ Chinese Acad Sci, Beijing, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Zhongyun,Wang, Lu,Qiao, Huarui,et al. Cryo-EM structure of the full-length LGR4-RSPOs complex and a targeting nanobody for anti-obesity therapy[J]. NATURE COMMUNICATIONS,2025,16(1):17.
APA Zhang, Zhongyun.,Wang, Lu.,Qiao, Huarui.,Jiang, Haowen.,Guo, Shaojue.,...&Geng, Yong.(2025).Cryo-EM structure of the full-length LGR4-RSPOs complex and a targeting nanobody for anti-obesity therapy.NATURE COMMUNICATIONS,16(1),17.
MLA Zhang, Zhongyun,et al."Cryo-EM structure of the full-length LGR4-RSPOs complex and a targeting nanobody for anti-obesity therapy".NATURE COMMUNICATIONS 16.1(2025):17.

入库方式： OAI收割

来源：上海药物研究所

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