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- EMDB-39573: Cryo-EM structure of CXCR4 tetramer -

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Basic information

Entry
Database: EMDB / ID: EMD-39573
TitleCryo-EM structure of CXCR4 tetramer
Map data
Sample
  • Complex: Tetramer of CXC Chemokine Receptor type 4
    • Protein or peptide: C-X-C chemokine receptor type 4
  • Ligand: CHOLESTEROL
KeywordsChemokine receptor / CXCR4 / G protein-coupled receptor / MEMBRANE PROTEIN
Function / homology
Function and homology information


C-X-C motif chemokine 12 receptor activity / regulation of viral process / positive regulation of vascular wound healing / positive regulation of macrophage migration inhibitory factor signaling pathway / neuron recognition / telencephalon cell migration / positive regulation of mesenchymal stem cell migration / response to tacrolimus / response to ultrasound / Specification of primordial germ cells ...C-X-C motif chemokine 12 receptor activity / regulation of viral process / positive regulation of vascular wound healing / positive regulation of macrophage migration inhibitory factor signaling pathway / neuron recognition / telencephalon cell migration / positive regulation of mesenchymal stem cell migration / response to tacrolimus / response to ultrasound / Specification of primordial germ cells / CXCL12-activated CXCR4 signaling pathway / myosin light chain binding / myelin maintenance / C-X-C chemokine receptor activity / regulation of programmed cell death / positive regulation of vasculature development / endothelial tube morphogenesis / endothelial cell differentiation / Signaling by ROBO receptors / regulation of chemotaxis / positive regulation of dendrite extension / Formation of definitive endoderm / C-C chemokine receptor activity / positive regulation of chemotaxis / C-C chemokine binding / Developmental Lineage of Pancreatic Acinar Cells / Chemokine receptors bind chemokines / anchoring junction / dendritic cell chemotaxis / epithelial cell development / cellular response to cytokine stimulus / small molecule binding / cell leading edge / detection of temperature stimulus involved in sensory perception of pain / positive regulation of oligodendrocyte differentiation / regulation of calcium ion transport / Binding and entry of HIV virion / detection of mechanical stimulus involved in sensory perception of pain / regulation of cell adhesion / coreceptor activity / cardiac muscle contraction / neurogenesis / ubiquitin binding / response to activity / cell chemotaxis / calcium-mediated signaling / G protein-coupled receptor activity / brain development / response to virus / neuron migration / late endosome / cellular response to xenobiotic stimulus / actin binding / positive regulation of cold-induced thermogenesis / virus receptor activity / positive regulation of cytosolic calcium ion concentration / cytoplasmic vesicle / G alpha (i) signalling events / early endosome / response to hypoxia / lysosome / immune response / positive regulation of cell migration / G protein-coupled receptor signaling pathway / inflammatory response / external side of plasma membrane / apoptotic process / ubiquitin protein ligase binding / cell surface / protein-containing complex / extracellular exosome / plasma membrane / cytoplasm
Similarity search - Function
CXC chemokine receptor 4 N-terminal domain / CXCR4 Chemokine receptor N terminal / CXC chemokine receptor 4/atypical chemokine receptor 2 / Chemokine receptor family / : / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family)
Similarity search - Domain/homology
C-X-C chemokine receptor type 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.01 Å
AuthorsLiu A / Liu Y
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cell Rep / Year: 2025
Title: Structural basis of CXCR4 assembly and regulation.
Authors: Aijun Liu / Yezhou Liu / Richard D Ye /
Abstract: CXC chemokine receptor 4 (CXCR4) is a well-established drug target and a key representative of the chemokine receptor family. Chemokine receptors tend to assemble, and this assembly plays a critical ...CXC chemokine receptor 4 (CXCR4) is a well-established drug target and a key representative of the chemokine receptor family. Chemokine receptors tend to assemble, and this assembly plays a critical role in regulating their functions. However, structural information regarding the organization of these receptors remains limited. Here, we present the cryoelectron microscopy (cryo-EM) structure of a CXCR4 homo-tetramer. In this tetramer, each protomer interfaces with adjacent protomers via TM1/2 and TM5/6/7, aligning at a 90° angle to assemble into a C4 rotationally symmetric arrangement. Each protomer allosterically regulates the others, with Q272 in the ECL3 loop interacting with K38 (TM1) and V99 (TM2) of the adjacent protomer, resulting in a mutually inhibitory configuration. These findings reveal an allosteric and antagonistic mechanism that prevents excessive activation, providing a structural framework for understanding the molecular mechanisms driving CXCR4 self-assembly and offering insights that could inspire further therapeutic strategies.
History
DepositionMar 26, 2024-
Header (metadata) releaseMar 5, 2025-
Map releaseMar 5, 2025-
UpdateMar 5, 2025-
Current statusMar 5, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_39573.png

Downloads & links

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Map

FileDownload / File: emd_39573.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 320 pix.
= 272. Å		0.85 Å/pix.
x 320 pix.
= 272. Å		0.85 Å/pix.
x 320 pix.
= 272. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.35
Minimum - Maximum-2.6196055 - 3.7084532
Average (Standard dev.)0.00033334715 (±0.10255767)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 272.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_39573_half_map_1.map
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Half map: #1

Fileemd_39573_half_map_2.map
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Sample components

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Entire : Tetramer of CXC Chemokine Receptor type 4

EntireName: Tetramer of CXC Chemokine Receptor type 4
Components
  • Complex: Tetramer of CXC Chemokine Receptor type 4
    • Protein or peptide: C-X-C chemokine receptor type 4
  • Ligand: CHOLESTEROL

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Supramolecule #1: Tetramer of CXC Chemokine Receptor type 4

SupramoleculeName: Tetramer of CXC Chemokine Receptor type 4 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: C-X-C chemokine receptor type 4

MacromoleculeName: C-X-C chemokine receptor type 4 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.656199 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: EGISIYTSDN YTEEMGSGDY DSMKEPCFRE ENANFNKIFL PTIYSIIFLT GIVGNGLVIL VMGYQKKLRS MTDKYRLHLS VADLLFVIT LPFWAVDAVA NWYFGNFLCK AVHVIYTVNL YSSVLILAFI SLDRYLAIVH ATNSQRPRKL LAEKVVYVGV W IPALLLTI ...String:
EGISIYTSDN YTEEMGSGDY DSMKEPCFRE ENANFNKIFL PTIYSIIFLT GIVGNGLVIL VMGYQKKLRS MTDKYRLHLS VADLLFVIT LPFWAVDAVA NWYFGNFLCK AVHVIYTVNL YSSVLILAFI SLDRYLAIVH ATNSQRPRKL LAEKVVYVGV W IPALLLTI PDFIFANVSE ADDRYICDRF YPNDLWVVVF QFQHIMVGLI LPGIVILSCY CIIISKLSHS KGHQKRKALK TT VILILAF FACWLPYYIG ISIDSFILLE IIKQGCEFEN TVHKWISITE ALAFFHCCLN PILYAFLGAK FKTSAQHALT SVS RGSSLK ILSKGKRGGH SSVSTESESS SFHSS

UniProtKB: C-X-C chemokine receptor type 4

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Macromolecule #2: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 2 / Number of copies: 20 / 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 TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 52.0 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: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1626680
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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