Cryo-EM structure of the full-length LGR4-RSPOs complex and a targeting nanobody for anti-obesity therapy

Zhongyun Zhang, Lu Wang, Huarui Qiao, Haowen Jiang, Shaojue Guo, Yuying Li, Ningning Zhang, Tengjie Geng, Qianqian Cui, Zhongyun Lan, Jie Hong, Weiqiong Gu, Ruixin Liu, Guang Ning (), Jia Li (), Jiqiu Wang () and Yong Geng ()
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Zhongyun Zhang: Shanghai Jiao Tong University School of Medicine
Lu Wang: Chinese Academy of Sciences
Huarui Qiao: Chinese Academy of Sciences
Haowen Jiang: Chinese Academy of Sciences
Shaojue Guo: Chinese Academy of Sciences
Yuying Li: Chinese Academy of Sciences
Ningning Zhang: Shanghai Jiao Tong University School of Medicine
Tengjie Geng: Chinese Academy of Sciences
Qianqian Cui: Chinese Academy of Sciences
Zhongyun Lan: Chinese Academy of Sciences
Jie Hong: Shanghai Jiao Tong University School of Medicine
Weiqiong Gu: Shanghai Jiao Tong University School of Medicine
Ruixin Liu: Shanghai Jiao Tong University School of Medicine
Guang Ning: Shanghai Jiao Tong University School of Medicine
Jia Li: Chinese Academy of Sciences
Jiqiu Wang: Shanghai Jiao Tong University School of Medicine
Yong Geng: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63410-5

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