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- EMDB-38307: the pentamerA complex of LGR4-RSPO2-ZNRF3(delta RING) -

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Basic information

Entry
Database: EMDB / ID: EMD-38307
Titlethe pentamerA complex of LGR4-RSPO2-ZNRF3(delta RING)
Map data
Sample
  • Complex: the pentamer A complex of LGR4-RSPO2-ZNRF3(delta RING domain)
    • Protein or peptide: Leucine-rich repeat-containing G-protein coupled receptor 4
    • Protein or peptide: nanobody Nb52
    • Protein or peptide: E3 ubiquitin-protein ligase ZNRF3
    • Protein or peptide: R-spondin-2
KeywordsLGR4-RSPO2-ZNRF3(delta RING) / 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 / Wnt receptor catabolic process / metanephric glomerulus development / metanephric nephron tubule morphogenesis / negative regulation of non-canonical Wnt signaling pathway / epithelial cell proliferation involved in renal tubule morphogenesis / Regulation of FZD by ubiquitination ...trachea cartilage morphogenesis / negative regulation of odontogenesis of dentin-containing tooth / lung growth / regulation of Wnt signaling pathway, planar cell polarity pathway / Wnt receptor catabolic process / metanephric glomerulus development / metanephric nephron tubule morphogenesis / negative regulation of non-canonical Wnt signaling pathway / epithelial cell proliferation involved in renal tubule morphogenesis / Regulation of FZD by ubiquitination / protein-hormone receptor activity / intestinal stem cell homeostasis / negative regulation of toll-like receptor signaling pathway / positive regulation of branching involved in ureteric bud morphogenesis / male genitalia development / dopaminergic neuron differentiation / bone remodeling / frizzled binding / embryonic forelimb morphogenesis / embryonic hindlimb morphogenesis / digestive tract development / 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: 3.21 Å
AuthorsGeng Y / Wang L
Funding support1 items
OrganizationGrant numberCountry
Not funded
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
DepositionDec 14, 2023-
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_38307.png

Downloads & links

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Map

FileDownload / File: emd_38307.map.gz / Format: CCP4 / Size: 178 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 360 pix.
= 385.56 Å		1.07 Å/pix.
x 360 pix.
= 385.56 Å		1.07 Å/pix.
x 360 pix.
= 385.56 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.071 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.22805925 - 0.39276302
Average (Standard dev.)-0.00039834582 (±0.0077023823)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 385.56 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_38307_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_38307_half_map_2.map
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Sample components

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Entire : the pentamer A complex of LGR4-RSPO2-ZNRF3(delta RING domain)

EntireName: the pentamer A complex of LGR4-RSPO2-ZNRF3(delta RING domain)
Components
  • Complex: the pentamer A complex of LGR4-RSPO2-ZNRF3(delta RING domain)
    • Protein or peptide: Leucine-rich repeat-containing G-protein coupled receptor 4
    • Protein or peptide: nanobody Nb52
    • Protein or peptide: E3 ubiquitin-protein ligase ZNRF3
    • Protein or peptide: R-spondin-2

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Supramolecule #1: the pentamer A complex of LGR4-RSPO2-ZNRF3(delta RING domain)

SupramoleculeName: the pentamer A complex of LGR4-RSPO2-ZNRF3(delta RING domain)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
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: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 104.565656 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPGPLGLLCF LALGLLGSAG PSGAAPPLCA APCSCDGDRR VDCSGKGLTA VPEGLSAFTQ ALDISMNNIT QLPEDAFKNF PFLEELQLA GNDLSFIHPK ALSGLKELKV LTLQNNQLKT VPSEAIRGLS ALQSLRLDAN HITSVPEDSF EGLVQLRHLW L DDNSLTEV ...String:
MPGPLGLLCF LALGLLGSAG PSGAAPPLCA APCSCDGDRR VDCSGKGLTA VPEGLSAFTQ ALDISMNNIT QLPEDAFKNF PFLEELQLA GNDLSFIHPK ALSGLKELKV LTLQNNQLKT VPSEAIRGLS ALQSLRLDAN HITSVPEDSF EGLVQLRHLW L DDNSLTEV PVHPLSNLPT LQALTLALNK ISSIPDFAFT NLSSLVVLHL HNNKIRSLSQ HCFDGLDNLE TLDLNYNNLG EF PQAIKAL PSLKELGFHS NSISVIPDGA FDGNPLLRTI HLYDNPLSFV GNSAFHNLSD LHSLVIRGAS MVQQFPNLTG TVH LESLTL TGTKISSIPN NLCQEQKMLR TLDLSYNNIR DLPSFNGCHA LEEISLQRNQ IYQIKEGTFQ GLISLRILDL SRNL IHEIH SRAFATLGPI TNLDVSFNEL TSFPTEGLNG LNQLKLVGNF KLKEALAAKD FVNLRSLSVP YAYQCCAFWG CDSYA NLNT EDNSLQDHSV AQEKGTADAA NVTSTLENEE HSQIIIHCTP STGAFKPCEY LLGSWMIRLT VWFIFLVALF FNLLVI LTT FASCTSLPSS KLFIGLISVS NLFMGIYTGI LTFLDAVSWG RFAEFGIWWE TGSGCKVAGF LAVFSSESAI FLLMLAT VE RSLSAKDIMK NGKSNHLKQF RVAALLAFLG ATVAGCFPLF HRGEYSASPL CLPFPTGETP SLGFTVTLVL LNSLAFLL M AVIYTKLYCN LEKEDLSENS QSSMIKHVAW LIFTNCIFFC PVAFFSFAPL ITAISISPEI MKSVTLIFFP LPACLNPVL YVFFNPKFKE DWKLLKRRVT KKSGSVSVSI SSQGGCLEQD FYYDCGMYSH LQGNLTVCDC CESFLLTKPV SCKHLIKSHS CPALAVASC QRPEGYWSDC GTQSAHSDYA DEEDSFVSDS SDQVQACGRA CFYQSRGFPL VRYAYNLPRV KD

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

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Macromolecule #2: nanobody Nb52

MacromoleculeName: nanobody Nb52 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / 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 #3: E3 ubiquitin-protein ligase ZNRF3

MacromoleculeName: E3 ubiquitin-protein ligase ZNRF3 / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO / EC number: RING-type E3 ubiquitin transferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 100.703906 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MRPRSGGRPG ATGRRRRRLR RRPRGLRCSR LPPPPPLPLL LGLLLAAAGP GAARAKETAF VEVVLFESSP SGDYTTYTTG LTGRFSRAG ATLSAEGEIV QMHPLGLCNN NDEEDLYEYG WVGVVKLEQP ELDPKPCLTV LGKAKRAVQR GATAVIFDVS E NPEAIDQL ...String:
MRPRSGGRPG ATGRRRRRLR RRPRGLRCSR LPPPPPLPLL LGLLLAAAGP GAARAKETAF VEVVLFESSP SGDYTTYTTG LTGRFSRAG ATLSAEGEIV QMHPLGLCNN NDEEDLYEYG WVGVVKLEQP ELDPKPCLTV LGKAKRAVQR GATAVIFDVS E NPEAIDQL NQGSEDPLKR PVVYVKGADA IKLMNIVNKQ KVARARIQHR PPRQPTEYFD MGIFLAFFVV VSLVCLILLV KI KLKQRRS QNSMNRLAVQ ALEKMETRKF NSKSKGRREG SCGALDTLSS SSTSDCAICL EKYIDGEELR VIPCTHRFHR KCV DPWLLQ HHTCPHCRHN IIEQKGNPSA VCVETSNLSR GRQQRVTLPV HYPGRVHRTN AIPAYPTRTS MDSHGNPVTL LTMD RHGEQ SLYSPQTPAY IRSYPPLHLD HSLAAHRCGL EHRAYSPAHP FRRPKLSGRS FSKAACFSQY ETMYQHYYFQ GLSYP EQEG QSPPSLAPRG PARAFPPSGS GSLLFPTVVH VAPPSHLESG STSSFSCYHG HRSVCSGYLA DCPGSDSSSS SSSGQC HCS SSDSVVDCTE VSNQGVYGSC STFRSSLSSD YDPFIYRSRS PCRASEAGGS GSSGRGPALC FEGSPPPEEL PAVHSHG AG RGEPWPGPAS PSGDQVSTCS LEMNYSSNSS LEHRGPNSST SEVGLEASPG AAPDLRRTWK GGHELPSCAC CCEPQPSP A GPSAGAAGSS TLFLGPHLYE GSGPAGGEPQ SGSSQGLYGL HPDHLPRTDG VKYEGLPCCF YEEKQVARGG GGGSGCYTE DYSVSVQYTL TEEPPPGCYP GARDLSQRIP IIPEDVDCDL GLPSDCQGTH SLGSWGGTRG PDTPRPHRGL GATREEERAL CCQARALLR PGCPPEEAGA VRANFPSALQ DTQESSTTAT EAAGPRSHSA DSSSPGA

UniProtKB: E3 ubiquitin-protein ligase ZNRF3

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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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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 F30
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 1.944 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Tecnai F30 / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.21 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 73170
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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