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- EMDB-48218: cryoEM structure of hCXCR4 tetramer bound to HIV-2/gp120/V3 loop -

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Basic information

Entry
Database: EMDB / ID: EMD-48218
TitlecryoEM structure of hCXCR4 tetramer bound to HIV-2/gp120/V3 loop
Map dataCXCR4_HIV-2/gp120/V3 loop density map
Sample
  • Complex: hCXCR4 tetramer bound to monomeric HIV-2/gp120/V3 loop
    • Protein or peptide: C-X-C chemokine receptor type 4
    • Protein or peptide: Surface protein gp120
KeywordsHIV-2 gp120 / V3 loop / hCXCR4 / SIGNALING PROTEIN
Function / homology
Function and homology information


C-X-C motif chemokine 12 receptor activity / positive regulation of macrophage migration inhibitory factor signaling pathway / myosin light chain binding / CXCL12-activated CXCR4 signaling pathway / Specification of primordial germ cells / myelin maintenance / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / C-X-C chemokine receptor activity / positive regulation of vasculature development / Signaling by ROBO receptors ...C-X-C motif chemokine 12 receptor activity / positive regulation of macrophage migration inhibitory factor signaling pathway / myosin light chain binding / CXCL12-activated CXCR4 signaling pathway / Specification of primordial germ cells / myelin maintenance / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / C-X-C chemokine receptor activity / positive regulation of vasculature development / Signaling by ROBO receptors / Formation of definitive endoderm / C-C chemokine receptor activity / C-C chemokine binding / anchoring junction / Chemokine receptors bind chemokines / dendritic cell chemotaxis / cellular response to cytokine stimulus / cell leading edge / positive regulation of oligodendrocyte differentiation / Binding and entry of HIV virion / regulation of cell adhesion / coreceptor activity / neurogenesis / host cell endosome membrane / cell chemotaxis / ubiquitin binding / calcium-mediated signaling / brain development / G protein-coupled receptor activity / response to virus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / late endosome / positive regulation of cold-induced thermogenesis / virus receptor activity / positive regulation of cytosolic calcium ion concentration / actin binding / cytoplasmic vesicle / clathrin-dependent endocytosis of virus by host cell / G alpha (i) signalling events / symbiont-mediated-mediated suppression of host tetherin activity / early endosome / response to hypoxia / lysosome / symbiont-mediated suppression of host innate immune response / positive regulation of cell migration / immune response / G protein-coupled receptor signaling pathway / inflammatory response / external side of plasma membrane / fusion of virus membrane with host endosome membrane / apoptotic process / viral envelope / ubiquitin protein ligase binding / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / 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 / : / Retroviral envelope protein / Retroviral envelope protein GP41-like / Gp120 core superfamily / Envelope glycoprotein GP120 / Human immunodeficiency virus 1, envelope glycoprotein Gp120 ...CXC chemokine receptor 4 N-terminal domain / CXCR4 Chemokine receptor N terminal / CXC chemokine receptor 4/atypical chemokine receptor 2 / Chemokine receptor family / : / Retroviral envelope protein / Retroviral envelope protein GP41-like / Gp120 core superfamily / Envelope glycoprotein GP120 / Human immunodeficiency virus 1, envelope glycoprotein Gp120 / G-protein coupled receptors family 1 signature. / 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
Envelope glycoprotein gp160 / C-X-C chemokine receptor type 4
Similarity search - Component
Biological speciesVirus-associated RNAs / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.57 Å
AuthorsZhang Z / Patel DJ
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)P30 CA008748 United States
CitationJournal: Nat Commun / Year: 2025
Title: CXCR4 mediated recognition of HIV envelope spike and inhibition by CXCL12.
Authors: Zhiying Zhang / Hongwei Zhang / Lyuqin Zheng / Shihua Chen / Shuo Du / Junyu Xiao / Dinshaw J Patel /
Abstract: CCR5 and CXCR4 both act as HIV co-receptors, though CXCR4 is less explored. CXCR4 binds the chemokine CXCL12 to regulate cellular processes and mediate HIV entry, a process that CXCL12 inhibits. ...CCR5 and CXCR4 both act as HIV co-receptors, though CXCR4 is less explored. CXCR4 binds the chemokine CXCL12 to regulate cellular processes and mediate HIV entry, a process that CXCL12 inhibits. Using cryo-EM, we investigate HIV-2 envelope (Env) spike recognition by CXCR4 and how CXCL12 inhibit this interaction. We discover that CXCR4 unexpected forms a tetramer, both alone and in complex. It binds CXCL12 with 4:8 and 8:8 stoichiometries, with the CXCL12 N-terminus inserting into the CXCR4 pocket. Structures of CXCR4-gp120 complex show one or two gp120 molecules per CXCR4 tetramer, with the V3 loop occupying the major sub-pocket of CXCR4 through deep embedment of its GFKF motif. The CXCL12 N-terminus chashes with gp120 V3 loops, explain its inhibitory effect. Docking analyses of other HIV antagonists further clarify their mechanisms. The CXCR4-gp120 model illustrate how V3 loop residues define co-receptor specificity, offering insights into co-receptor switching and therapeutic design.
History
DepositionDec 7, 2024-
Header (metadata) releaseSep 10, 2025-
Map releaseSep 10, 2025-
UpdateMar 25, 2026-
Current statusMar 25, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48218.png

Downloads & links

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Map

FileDownload / File: emd_48218.map.gz / Format: CCP4 / Size: 282.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCXCR4_HIV-2/gp120/V3 loop density map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 420 pix.
= 304.5 Å		0.73 Å/pix.
x 420 pix.
= 304.5 Å		0.73 Å/pix.
x 420 pix.
= 304.5 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.725 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.195
Minimum - Maximum-0.38184756 - 0.7228063
Average (Standard dev.)0.0014510509 (±0.025928894)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions420420420
Spacing420420420
CellA=B=C: 304.5 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: CXCR4 HIV-2/gp120/V3 loop density halfB map

Fileemd_48218_half_map_1.map
AnnotationCXCR4_HIV-2/gp120/V3 loop density halfB map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: CXCR4 HIV-2/gp120/V3 loop density halfA map

Fileemd_48218_half_map_2.map
AnnotationCXCR4_HIV-2/gp120/V3 loop density halfA map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : hCXCR4 tetramer bound to monomeric HIV-2/gp120/V3 loop

EntireName: hCXCR4 tetramer bound to monomeric HIV-2/gp120/V3 loop
Components
  • Complex: hCXCR4 tetramer bound to monomeric HIV-2/gp120/V3 loop
    • Protein or peptide: C-X-C chemokine receptor type 4
    • Protein or peptide: Surface protein gp120

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Supramolecule #1: hCXCR4 tetramer bound to monomeric HIV-2/gp120/V3 loop

SupramoleculeName: hCXCR4 tetramer bound to monomeric HIV-2/gp120/V3 loop
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Virus-associated RNAs

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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: 40.784359 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEGISIYTSD NYTEEMGSGD YDSMKEPCFR EENANFNKIF LPTIYSIIFL TGIVGNGLVI LVMGYQKKLR SMTDKYRLHL SVADLLFVI TLPFWAVDAV ANWYFGNFLC KAVHVIYTVN LYSSVLILAF ISLDRYLAIV HATNSQRPRK LLAEKVVYVG V WIPALLLT ...String:
MEGISIYTSD NYTEEMGSGD YDSMKEPCFR EENANFNKIF LPTIYSIIFL TGIVGNGLVI LVMGYQKKLR SMTDKYRLHL SVADLLFVI TLPFWAVDAV ANWYFGNFLC KAVHVIYTVN LYSSVLILAF ISLDRYLAIV HATNSQRPRK LLAEKVVYVG V WIPALLLT IPDFIFANVS EADDRYICDR FYPNDLWVVV FQFQHIMVGL ILPGIVILSC YCIIISKLSH SKGHQKRKAL KT TVILILA FFACWLPYYI GISIDSFILL EIIKQGCEFE NTVHKWISIT EALAFFHCCL NPILYAFLGA KFKTSAQHAL TSV SRGSSL KILSKGKRGG HSSVSTESES SSFHSSDYKD DDDK

UniProtKB: C-X-C chemokine receptor type 4

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Macromolecule #2: Surface protein gp120

MacromoleculeName: Surface protein gp120 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Virus-associated RNAs
Molecular weightTheoretical: 2.261726 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
NKTVLPIMSG FKFHSKPVIN

UniProtKB: Envelope glycoprotein gp160

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 60.21 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: Alphafold2
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.57 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 117147
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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