9UOK
Structure of the complex of LGR4_ECD with Norrin
Summary for 9UOK
| Entry DOI | 10.2210/pdb9uok/pdb |
| EMDB information | 64380 |
| Descriptor | MB52, Leucine-rich repeat-containing G-protein coupled receptor 4, Norrin,Immunoglobulin gamma-1 heavy chain (3 entities in total) |
| Functional Keywords | lgr4 norrin, membrane protein |
| Biological source | Camelus ferus More |
| Total number of polymer chains | 4 |
| Total formula weight | 255290.75 |
| Authors | Geng, Y.,Hu, F.Z.,Qiao, H.R. (deposition date: 2025-04-25, release date: 2025-07-16, Last modification date: 2026-02-18) |
| Primary citation | Qiao, H.,Hu, F.,Wang, Y.,Wang, L.,Zhou, S.,Guo, S.,Xu, Y.,Xu, J.,Cui, Q.,Yang, Q.,Xu, H.E.,Zhu, J.,Geng, Y. Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/ beta-catenin signaling. Nat Commun, 16:6256-6256, 2025 Cited by PubMed Abstract: The Wnt/β-catenin pathway requires precise regulation for proper development and tissue homeostasis, yet the structural mechanisms enabling its fine-tuned control remain incompletely understood. Here, we reveal how LGR4 achieves differential signaling outcomes through distinct recognition of two key modulators: Norrin and R-spondins (RSPOs). Using cryo-electron microscopy, we determined the structure of full-length LGR4 bound to Norrin in a 2:2 stoichiometry, revealing a molecular bridging mechanism where Norrin dimer connect two LGR4 protomers in a spatial arrangement fundamentally distinct from the LGR4-RSPO2-ZNRF3 complex. Notably, Norrin binding to LGR4 sterically hinders simultaneous interaction with the Frizzled4 receptor, establishing a regulatory checkpoint in Wnt signaling. The partially overlapping binding sites for Norrin and RSPOs on LGR4 enable mutually exclusive interactions that drive distinct signaling outcomes. Disease-linked mutations map to distinct functional regions: those disrupting LGR4 interaction are associated with familial exudative vitreoretinopathy (FEVR), while others impairing Frizzled4 binding are linked to Norrie disease. Furthermore, we developed a high-affinity nanobody that blocks both Norrin and RSPO binding to LGR4, providing a potential tool for therapeutic intervention. These findings elucidate the structural basis of LGR4's dual signaling roles and lay the groundwork for therapeutic strategies targeting Wnt-related diseases. PubMed: 40624078DOI: 10.1038/s41467-025-61545-z PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.05 Å) |
Structure validation
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