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- PDB-9uok: Structure of the complex of LGR4_ECD with Norrin -

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Basic information

Entry
Database: PDB / ID: 9uok
TitleStructure of the complex of LGR4_ECD with Norrin
Components
  • Leucine-rich repeat-containing G-protein coupled receptor 4
  • MB52
  • Norrin,Immunoglobulin gamma-1 heavy chain
KeywordsMEMBRANE PROTEIN / LGR4 Norrin
Function / homology
Function and homology information


retina blood vessel maintenance / cone retinal bipolar cell differentiation / Norrin signaling pathway / extracellular matrix-cell signaling / retinal rod cell differentiation / re-entry into mitotic cell cycle / retinal blood vessel morphogenesis / metanephric glomerulus development / metanephric nephron tubule morphogenesis / epithelial cell proliferation involved in renal tubule morphogenesis ...retina blood vessel maintenance / cone retinal bipolar cell differentiation / Norrin signaling pathway / extracellular matrix-cell signaling / retinal rod cell differentiation / re-entry into mitotic cell cycle / retinal blood vessel morphogenesis / metanephric glomerulus development / metanephric nephron tubule morphogenesis / epithelial cell proliferation involved in renal tubule morphogenesis / protein-hormone receptor activity / glycine metabolic process / intestinal stem cell homeostasis / retina layer formation / retinal pigment epithelium development / endothelial cell differentiation / microglial cell proliferation / dendritic spine development / negative regulation of toll-like receptor signaling pathway / establishment of blood-retinal barrier / vacuole organization / positive regulation of branching involved in ureteric bud morphogenesis / male genitalia development / microglia differentiation / protein targeting to lysosome / establishment of blood-brain barrier / bone remodeling / frizzled binding / optic nerve development / retinal ganglion cell axon guidance / lens development in camera-type eye / digestive tract development / negative regulation of cold-induced thermogenesis / negative regulation of cytokine production / ubiquitin-dependent endocytosis / smoothened signaling pathway / bone mineralization / exploration behavior / decidualization / action potential / hair follicle development / blood vessel remodeling / immunoglobulin complex / canonical Wnt signaling pathway / response to axon injury / : / tricarboxylic acid cycle / visual perception / transforming growth factor beta receptor signaling pathway / Regulation of FZD by ubiquitination / cytokine activity / glutathione metabolic process / circadian regulation of gene expression / G protein-coupled receptor activity / Wnt signaling pathway / osteoblast differentiation / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / nervous system development / mitotic cell cycle / neuron apoptotic process / angiogenesis / spermatogenesis / cellular response to hypoxia / transcription by RNA polymerase II / adaptive immune response / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein ubiquitination / inflammatory response / innate immune response / positive regulation of DNA-templated transcription / cell surface / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / : / extracellular region / plasma membrane
Similarity search - Function
Norrie disease protein / Glycoprotein hormone subunit beta / Cystine-knot domain / Glycoprotein hormone receptor family / C-terminal cystine knot signature. / C-terminal cystine knot domain profile. / Cystine knot, C-terminal / C-terminal cystine knot-like domain (CTCK) / Leucine rich repeat N-terminal domain / Leucine-rich repeat N-terminal domain ...Norrie disease protein / Glycoprotein hormone subunit beta / Cystine-knot domain / Glycoprotein hormone receptor family / C-terminal cystine knot signature. / C-terminal cystine knot domain profile. / Cystine knot, C-terminal / C-terminal cystine knot-like domain (CTCK) / Leucine rich repeat N-terminal domain / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Leucine Rich Repeat / Leucine-rich repeats, bacterial type / Cystine-knot cytokine / Leucine-rich repeat, SDS22-like subfamily / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / : / Leucine-rich repeat profile. / Leucine-rich repeat / Immunoglobulin V-Type / Immunoglobulin V-set domain / Leucine-rich repeat domain superfamily / Immunoglobulin V-set domain / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Immunoglobulin gamma-1 heavy chain / Norrin / Leucine-rich repeat-containing G-protein coupled receptor 4
Similarity search - Component
Biological speciesCamelus ferus (Wild Bactrian camel)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.05 Å
AuthorsGeng, Y. / Hu, F.Z. / Qiao, H.R.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2025
Title: Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling.
Authors: Huarui Qiao / Fangzheng Hu / Yiang Wang / Lu Wang / Siyu Zhou / Shaojue Guo / Yiwen Xu / Jianfeng Xu / Qianqian Cui / Qilun Yang / H Eric Xu / Jianwei Zhu / Yong Geng /
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. ...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.
History
DepositionApr 25, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 16, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: MB52
C: Leucine-rich repeat-containing G-protein coupled receptor 4
E: Norrin,Immunoglobulin gamma-1 heavy chain
F: Norrin,Immunoglobulin gamma-1 heavy chain


Theoretical massNumber of molelcules
Total (without water)255,2914
Polymers255,2914
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Antibody MB52


Mass: 59266.367 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Camelus ferus (Wild Bactrian camel) / Production host: Escherichia coli (E. coli)
#2: Protein Leucine-rich repeat-containing G-protein coupled receptor 4 / G-protein coupled receptor 48


Mass: 105397.508 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LGR4, GPR48 / Production host: Homo sapiens (human) / References: UniProt: Q9BXB1
#3: Antibody Norrin,Immunoglobulin gamma-1 heavy chain / Norrie disease protein / X-linked exudative vitreoretinopathy 2 protein / Immunoglobulin gamma-1 ...Norrie disease protein / X-linked exudative vitreoretinopathy 2 protein / Immunoglobulin gamma-1 heavy chain NIE


Mass: 45313.438 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NDP, EVR2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q00604, UniProt: P0DOX5
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Structure of the complex of LGR4_ECD with Norrin / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.05 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1196610 / Symmetry type: POINT
RefinementHighest resolution: 3.05 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0035969
ELECTRON MICROSCOPYf_angle_d0.7018081
ELECTRON MICROSCOPYf_dihedral_angle_d5.93822
ELECTRON MICROSCOPYf_chiral_restr0.045920
ELECTRON MICROSCOPYf_plane_restr0.0041045

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