8XUM

Structure of LGR4 with RSPO2

Summary for 8XUM

• Entry DOI: 10.2210/pdb8xum/pdb
• EMDB information: 38677
• Descriptor: MB52, Leucine-rich repeat-containing G-protein coupled receptor 4, R-spondin-2 (3 entities in total)
• Functional Keywords: lgr4, rspo2, membrane protein
• Biological source: Camelus bactrianus; More
• Total number of polymer chains: 3
• Total formula weight: 144925.06

Authors

Wang, L.,Geng, Y. (deposition date: 2024-01-13, release date: 2025-01-15, Last modification date: 2025-12-24)

Primary citation

Zhang, Z.,Wang, L.,Qiao, H.,Jiang, H.,Guo, S.,Li, Y.,Zhang, N.,Geng, T.,Cui, Q.,Lan, Z.,Hong, J.,Gu, W.,Liu, R.,Ning, G.,Li, J.,Wang, J.,Geng, Y.
Cryo-EM structure of the full-length LGR4-RSPOs complex and a targeting nanobody for anti-obesity therapy.
Nat Commun, 16:8406-8406, 2025

PubMed 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.

PubMed: 40998774
DOI: 10.1038/s41467-025-63410-5

Experimental method

ELECTRON MICROSCOPY (2.9 Å)