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- EMDB-38641: structure of LGR4 -

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Basic information

Entry
Database: EMDB / ID: EMD-38641
Titlestructure of LGR4
Map data
Sample
  • Complex: structure of LGR4
    • Protein or peptide: Leucine-rich repeat-containing G-protein coupled receptor 4
    • Protein or peptide: MB52
KeywordsLGR4 / MEMBRANE PROTEIN
Function / homology
Function and homology information


metanephric glomerulus development / metanephric nephron tubule morphogenesis / epithelial cell proliferation involved in renal tubule morphogenesis / 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 / bone remodeling / digestive tract development ...metanephric glomerulus development / metanephric nephron tubule morphogenesis / epithelial cell proliferation involved in renal tubule morphogenesis / 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 / bone remodeling / digestive tract development / negative regulation of cold-induced thermogenesis / negative regulation of cytokine production / bone mineralization / hair follicle development / Regulation of FZD by ubiquitination / 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 / spermatogenesis / innate immune response / plasma membrane
Similarity search - Function
Glycoprotein hormone receptor family / 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 / Leucine-rich repeat, SDS22-like subfamily / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily ...Glycoprotein hormone receptor family / 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 / 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 / Leucine-rich repeat domain superfamily / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile.
Similarity search - Domain/homology
Leucine-rich repeat-containing G-protein coupled receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human) / Camelus bactrianus (Bactrian camel)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsWang L / Geng Y
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2025
Title: Cryo-EM structure of the full-length LGR4-RSPOs complex and a targeting nanobody for anti-obesity therapy.
Authors: Zhongyun Zhang / Lu Wang / Huarui Qiao / Haowen Jiang / Shaojue Guo / Yuying Li / Ningning Zhang / Tengjie Geng / Qianqian Cui / Zhongyun Lan / Jie Hong / Weiqiong Gu / Ruixin Liu / Guang ...Authors: Zhongyun Zhang / Lu Wang / Huarui Qiao / Haowen Jiang / Shaojue Guo / Yuying Li / Ningning Zhang / Tengjie Geng / Qianqian Cui / Zhongyun Lan / Jie Hong / Weiqiong Gu / Ruixin Liu / Guang Ning / Jia Li / Jiqiu Wang / Yong Geng /
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 ...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.
History
DepositionJan 10, 2024-
Header (metadata) releaseJan 15, 2025-
Map releaseJan 15, 2025-
UpdateDec 24, 2025-
Current statusDec 24, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38641.png

Downloads & links

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Map

FileDownload / File: emd_38641.map.gz / Format: CCP4 / Size: 103 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 300 pix.
= 321.3 Å		1.07 Å/pix.
x 300 pix.
= 321.3 Å		1.07 Å/pix.
x 300 pix.
= 321.3 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.071 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.115
Minimum - Maximum-0.28015417 - 0.7240638
Average (Standard dev.)-0.00037162844 (±0.011440427)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 321.3 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_38641_half_map_1.map
Projections & Slices
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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_38641_half_map_2.map
Projections & Slices
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Sample components

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Entire : structure of LGR4

EntireName: structure of LGR4
Components
  • Complex: structure of LGR4
    • Protein or peptide: Leucine-rich repeat-containing G-protein coupled receptor 4
    • Protein or peptide: MB52

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Supramolecule #1: structure of LGR4

SupramoleculeName: structure of LGR4 / 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: MB52

MacromoleculeName: MB52 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Camelus bactrianus (Bactrian camel)
Molecular weightTheoretical: 12.003422 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GSLRLSCAAS GYTYSPYCMG WFRQAPGKAR EGVATVDLDG STIYADSVKG RFTISQDNAK NTLYLQMNSL KPEDTAMYYC ASRTRAGVT CGLNWAIFSY WGQGTQVTVS S

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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 TITAN
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

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1772142
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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