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- PDB-8xum: Structure of LGR4 with RSPO2 -

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Basic information

Entry
Database: PDB / ID: 8xum
TitleStructure of LGR4 with RSPO2
Components
  • Leucine-rich repeat-containing G-protein coupled receptor 4
  • MB52
  • R-spondin-2
KeywordsMEMBRANE PROTEIN / LGR4 / RSPO2
Function / homology
Function and homology information


trachea cartilage morphogenesis / negative regulation of odontogenesis of dentin-containing tooth / lung growth / 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 / BMP receptor binding ...trachea cartilage morphogenesis / negative regulation of odontogenesis of dentin-containing tooth / lung growth / 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 / BMP receptor binding / positive regulation of branching involved in ureteric bud morphogenesis / male genitalia development / dopaminergic neuron differentiation / bone remodeling / embryonic forelimb morphogenesis / embryonic hindlimb morphogenesis / digestive tract development / negative regulation of cold-induced thermogenesis / limb development / negative regulation of cytokine production / epithelial tube branching involved in lung morphogenesis / bone mineralization / hair follicle development / canonical Wnt signaling pathway / positive regulation of Wnt signaling pathway / 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 / heparin binding / spermatogenesis / signaling receptor binding / innate immune response / cell surface / extracellular space / extracellular region / plasma membrane
Similarity search - Function
R-spondin, Fu-CRD domain / : / Furin-like repeat, cysteine-rich / Glycoprotein hormone receptor family / 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 ...R-spondin, Fu-CRD domain / : / Furin-like repeat, cysteine-rich / Glycoprotein hormone receptor family / 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. / Growth factor receptor cysteine-rich domain superfamily / 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
R-spondin-2 / Leucine-rich repeat-containing G-protein coupled receptor 4
Similarity search - Component
Biological speciesCamelus bactrianus (Bactrian camel)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsWang, L. / Geng, Y.
Funding support1items
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 13, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 15, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: MB52
A: Leucine-rich repeat-containing G-protein coupled receptor 4
B: R-spondin-2


Theoretical massNumber of molelcules
Total (without water)144,9253
Polymers144,9253
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: 12003.422 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Camelus bactrianus (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: 104565.656 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: Protein R-spondin-2


Mass: 28355.986 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RSPO2 / Production host: Homo sapiens (human) / References: UniProt: Q6UXX9
Has ligand of interestY
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 LGR4 with RSPO2 / 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

MicroscopyModel: FEI TITAN
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm / Cs: 2.7 mm
Image recordingElectron dose: 1.944 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 2357026 / Symmetry type: POINT

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