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- EMDB-38982: LGR4-RSPO2-ZNRF3 (2:2:2) -

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Basic information

Entry
Database: EMDB / ID: EMD-38982
TitleLGR4-RSPO2-ZNRF3 (2:2:2)
Map data
Sample
  • Complex: The di-heterotrimer complex of LGR4-RSPO2-ZNRF3(delete RING domain)
    • Protein or peptide: Leucine-rich repeat-containing G-protein coupled receptor 4
    • Protein or peptide: E3 ubiquitin-protein ligase ZNRF3
    • Protein or peptide: MB52
    • Protein or peptide: R-spondin-2
  • Ligand: CHOLESTEROL
KeywordsLGR4 / RSPO2 / ZNRF3 / 2:2:2 / MEMBRANE PROTEIN
Function / homology
Function and homology information


trachea cartilage morphogenesis / negative regulation of odontogenesis of dentin-containing tooth / lung growth / regulation of Wnt signaling pathway, planar cell polarity pathway / metanephric glomerulus development / metanephric nephron tubule morphogenesis / Wnt receptor catabolic process / epithelial cell proliferation involved in renal tubule morphogenesis / negative regulation of non-canonical Wnt signaling pathway / protein-hormone receptor activity ...trachea cartilage morphogenesis / negative regulation of odontogenesis of dentin-containing tooth / lung growth / regulation of Wnt signaling pathway, planar cell polarity pathway / metanephric glomerulus development / metanephric nephron tubule morphogenesis / Wnt receptor catabolic process / epithelial cell proliferation involved in renal tubule morphogenesis / negative regulation of non-canonical Wnt signaling pathway / protein-hormone receptor activity / Regulation of FZD by ubiquitination / intestinal stem cell homeostasis / negative regulation of toll-like receptor signaling pathway / positive regulation of branching involved in ureteric bud morphogenesis / male genitalia development / bone remodeling / dopaminergic neuron differentiation / frizzled binding / embryonic forelimb morphogenesis / digestive tract development / embryonic hindlimb morphogenesis / limb development / negative regulation of cold-induced thermogenesis / negative regulation of cytokine production / epithelial tube branching involved in lung morphogenesis / bone mineralization / hair follicle development / canonical Wnt signaling pathway / Regulation of FZD by ubiquitination / stem cell proliferation / circadian regulation of gene expression / negative regulation of canonical Wnt signaling pathway / G protein-coupled receptor activity / RING-type E3 ubiquitin transferase / Wnt signaling pathway / ubiquitin-protein transferase activity / osteoblast differentiation / ubiquitin protein ligase activity / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / heparin binding / ubiquitin-dependent protein catabolic process / spermatogenesis / protein ubiquitination / signaling receptor binding / innate immune response / cell surface / extracellular region / zinc ion binding / plasma membrane
Similarity search - Function
Spondin-like TSP1 domain / Spondin-like TSP1 domain / E3 ubiquitin-protein ligase ZNRF3, Zinc finger, RING-type / ZNRF-3, ectodomain / ZNRF-3 Ectodomain / R-spondin, Fu-CRD domain / : / Furin-like repeat, cysteine-rich / : / Glycoprotein hormone receptor family ...Spondin-like TSP1 domain / Spondin-like TSP1 domain / E3 ubiquitin-protein ligase ZNRF3, Zinc finger, RING-type / ZNRF-3, ectodomain / ZNRF-3 Ectodomain / R-spondin, Fu-CRD domain / : / Furin-like repeat, cysteine-rich / : / Glycoprotein hormone receptor family / Ring finger domain / Leucine rich repeat N-terminal domain / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Thrombospondin type-1 (TSP1) repeat superfamily / Thrombospondin type-1 (TSP1) repeat profile. / Thrombospondin type 1 repeats / Thrombospondin type-1 (TSP1) repeat / Leucine Rich Repeat / Leucine-rich repeats, bacterial type / Leucine-rich repeat, SDS22-like subfamily / Furin-like repeat / Furin-like repeats / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Ring finger / Growth factor receptor cysteine-rich domain superfamily / Leucine-rich repeat / Leucine-rich repeat domain superfamily / Zinc finger RING-type profile. / Zinc finger, RING-type / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
R-spondin-2 / Leucine-rich repeat-containing G-protein coupled receptor 4 / E3 ubiquitin-protein ligase ZNRF3
Similarity search - Component
Biological speciesHomo sapiens (human) / Camelus bactrianus (Bactrian camel)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.38 Å
AuthorsWang L / Geng Y
Funding support China, 1 items
OrganizationGrant numberCountry
Not funded China
CitationJournal: Nat Commun / Year: 2025
Title: Structural insights into the LGR4-RSPO2-ZNRF3 complexes regulating WNT/β-catenin signaling.
Authors: Lu Wang / Fangzheng Hu / Qianqian Cui / Huarui Qiao / Lingyun Li / Tengjie Geng / Yuying Li / Zengchao Sun / Siyu Zhou / Zhongyun Lan / Shaojue Guo / Ying Hu / Jiqiu Wang / Qilun Yang / ...Authors: Lu Wang / Fangzheng Hu / Qianqian Cui / Huarui Qiao / Lingyun Li / Tengjie Geng / Yuying Li / Zengchao Sun / Siyu Zhou / Zhongyun Lan / Shaojue Guo / Ying Hu / Jiqiu Wang / Qilun Yang / Zenan Wang / Yuanyuan Dai / Yong Geng /
Abstract: WNT/β-catenin signaling plays key roles in development and cancer. ZNRF3/RNF43 modulates Frizzleds through ubiquitination, dampening WNT/β-catenin signaling. Conversely, RSPO1-4 binding to LGR4-6 ...WNT/β-catenin signaling plays key roles in development and cancer. ZNRF3/RNF43 modulates Frizzleds through ubiquitination, dampening WNT/β-catenin signaling. Conversely, RSPO1-4 binding to LGR4-6 and ZNRF3/RNF43 enhances WNT/β-catenin signaling. Here, we elucidate the overall landscape of architectures in multiple LGR4, RSPO2, and ZNRF3 assemblies, showcasing varying stoichiometries and arrangements. These structures reveal that LGR4 and RSPO2 capture distinct states of ZNRF3. The intrinsic heterogeneity of the LGR4-RSPO2-ZNRF3 assembly is influenced by LGR4 content. Particularly, in the assembly complex with a 2:2:2 ratio, two LGR4 protomers induce and stabilize the inactive state of ZNRF3, characterized by a wide inward-open conformation of two transmembrane helices (TM helices). This specific assembly promotes a stable complex, facilitating LGR4-induced endocytosis of ZNRF3. In contrast, the active dimeric ZNRF3, bound by a single LGR4, adopts a coiled-coil TM helices conformation and dimerization of RING domains. Our findings unveil how LGR4 content mediates diverse assemblies, leading to conformational rearrangements in ZNRF3 to regulate WNT/β-catenin signaling, and provide a structural foundation for drug development targeting Wnt-driven cancers.
History
DepositionFeb 2, 2024-
Header (metadata) releaseDec 4, 2024-
Map releaseDec 4, 2024-
UpdateJun 18, 2025-
Current statusJun 18, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38982.png

Downloads & links

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Map

FileDownload / File: emd_38982.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 512 pix.
= 548.352 Å		1.07 Å/pix.
x 512 pix.
= 548.352 Å		1.07 Å/pix.
x 512 pix.
= 548.352 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.071 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.05
Minimum - Maximum-0.21888979 - 0.4047121
Average (Standard dev.)-0.00014476756 (±0.00613346)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 548.352 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_38982_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_38982_half_map_2.map
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Sample components

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Entire : The di-heterotrimer complex of LGR4-RSPO2-ZNRF3(delete RING domain)

EntireName: The di-heterotrimer complex of LGR4-RSPO2-ZNRF3(delete RING domain)
Components
  • Complex: The di-heterotrimer complex of LGR4-RSPO2-ZNRF3(delete RING domain)
    • Protein or peptide: Leucine-rich repeat-containing G-protein coupled receptor 4
    • Protein or peptide: E3 ubiquitin-protein ligase ZNRF3
    • Protein or peptide: MB52
    • Protein or peptide: R-spondin-2
  • Ligand: CHOLESTEROL

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Supramolecule #1: The di-heterotrimer complex of LGR4-RSPO2-ZNRF3(delete RING domain)

SupramoleculeName: The di-heterotrimer complex of LGR4-RSPO2-ZNRF3(delete RING domain)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Leucine-rich repeat-containing G-protein coupled receptor 4

MacromoleculeName: Leucine-rich repeat-containing G-protein coupled receptor 4
type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 87.17 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: CSCDGDRRVD CSGKGLTAVP EGLSAFTQAL DISMNNITQL PEDAFANFPF LEELQLAGND LSFIHPKALS GLKELKVLTL QNNQLKTVP SEAIRGLSAL QSLRLDANHI TSVPEDSFEG LVQLRHLWLD DNSLTEVPVH PLSNLPTLQA LTLALNKISS I PDFAFTNL ...String:
CSCDGDRRVD CSGKGLTAVP EGLSAFTQAL DISMNNITQL PEDAFANFPF LEELQLAGND LSFIHPKALS GLKELKVLTL QNNQLKTVP SEAIRGLSAL QSLRLDANHI TSVPEDSFEG LVQLRHLWLD DNSLTEVPVH PLSNLPTLQA LTLALNKISS I PDFAFTNL SSLVVLHLHN NKIRSLSQHC FDGLDNLETL DLNYNNLGEF PQAIKALPSL KELGFHSNSI SVIPDGAFDG NP LLRTIHL YDNPLSFVGN SAFHNLSDLH SLVIRGASMV QQFPNLTGTV HLESLTLTGT KISSIPNNLC QEQKMLRTLD LSY NNIRDL PSFNGCHALE EISLQRNQIY QIKEGTFQGL ISLRILDLSR NLIHEIHSRA FATLGPITNL DVSFNELTSF PTEG LNGLN QLKLVGNFKL KEALAAKDFV NLRSLSVPYA YQCCAFWGCD SYANLNTEDN SLQDHSVAQE KGTADAANVT STLEN EEHS QIIIHCTPST GAFKPCEYLL GSWMIRLTVW FIFLVALFFN LLVILTTFAC ATSLPSSKLF IGLISVSNLF MGIYTG ILT FLDAVSWGRF AEFGIWWETG SGCKVAGFLA VFSSESAIFL LMLATVERSL SAKDIMKNGK SNHLKQFRVA ALLAFLG AT VAGCFPLFHR GEYSASPLCL PFPTGETPSL GFTVTLVLLN SLAFLLMAVI YTKLYCNLEK EDLSENSQSS MIKHVAWL I FTNCIFFCPV AFFSFAPLIT AISISPEIMK SVTLIFFPLP ACLNPVLYVF FNPKFKEDWK LLKRRVT

UniProtKB: Leucine-rich repeat-containing G-protein coupled receptor 4

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Macromolecule #2: E3 ubiquitin-protein ligase ZNRF3

MacromoleculeName: E3 ubiquitin-protein ligase ZNRF3 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO / EC number: RING-type E3 ubiquitin transferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 20.864059 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
KETAFVEVVL FESSPSGDYT TYTTGLTGRF SRAGATLSAE GEIVQMHPLG LCNNNDEEDL YEYGWVGVVK LEQPELDPKP CLTVLGKAK RAVQRGATAV IFDVSENPEA IDQLNQGSED PLKRPVVYVK GADAIKLMNI VNKQKVARAR IQHRPPRQPT E YFDMGIFL AFFVVVSLVC LILLVKIKLK

UniProtKB: E3 ubiquitin-protein ligase ZNRF3

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Macromolecule #3: MB52

MacromoleculeName: MB52 / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Camelus bactrianus (Bactrian camel)
Molecular weightTheoretical: 59.692801 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MKKIWLALAG LVLAFSASAQ VQLVESGGGL VQTKTTTSVI DTTNDAQNLL TQAQTIVNTL KDYCPILIAK SSSSNGGTNN ANTPSWQTA GGGKNSCATF GAEFSAASDM INNAQKIVQE TQQLSANQPK NITQPHNLNL NSPSSLTALA QKMLKNAQSQ A EILKLANQ ...String:
MKKIWLALAG LVLAFSASAQ VQLVESGGGL VQTKTTTSVI DTTNDAQNLL TQAQTIVNTL KDYCPILIAK SSSSNGGTNN ANTPSWQTA GGGKNSCATF GAEFSAASDM INNAQKIVQE TQQLSANQPK NITQPHNLNL NSPSSLTALA QKMLKNAQSQ A EILKLANQ VESDFNKLSS GHLKDYIGKC DASAISSANM TMQNQKNNWG NGCAGVEETQ SLLKTSAADF NNQTPQINQA QN LANTLIQ ELGNNPFRAS GGGSGGGGSG KLSDTYEQLS RLLTNDNGTN SKTSAQAINQ AVNNLNERAK TLAGGTTNSP AYQ ATLLAL RSVLGLWNSM GYAVICGGYT KSPGENNQKD FHYTDENGNG TTINCGGSTN SNGTHSYNGT NTLKADKNVS LSIE QYEKI HEAYQILSKA LKQAGLAPLN SKGEKLEAHV TTSKYGSLRL SCAASGYTYS PYCMGWFRQA PGKAREGVAT VDLDG STIY ADSVKGRFTI SQDNAKNTLY LQMNSLKPED TAMYYCASRT RAGVTCGLNW AIFSYWGQGT QVTVSSHHHH HHEPEA

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Macromolecule #4: R-spondin-2

MacromoleculeName: R-spondin-2 / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.63142 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
KGCLSCSKDN GCSRCQQKLF FFLRREGMRQ YGECLHSCPS GYYGHRAPDM NRCARCRIEN CDSCFSKDFC TKCKVGFYLH RGRCFDECP AGFAPLDETM EC

UniProtKB: R-spondin-2

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Macromolecule #5: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 2 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TECNAI ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 1.944 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: OTHER
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: OTHER / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.38 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 47438
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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