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- EMDB-48219: CXCR4-HIV-2/gp120-CD4 -

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Basic information

Entry
Database: EMDB / ID: EMD-48219
TitleCXCR4-HIV-2/gp120-CD4
Map datacryo-EM density map of CXCR4 bound to HIV-2/gp120-CD4 complex
Sample
  • Complex: cryoEM structure of CXCR4-HIV-2/gp120-CD4 complex
    • Protein or peptide: C-X-C chemokine receptor type 4
    • Protein or peptide: T-cell surface glycoprotein CD4
    • Protein or peptide: HIV-1/gp120
Keywordscxcr4 / HIV-2 gp120 / CD4 / D1-D2 / 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 / helper T cell enhancement of adaptive immune response / interleukin-16 binding / interleukin-16 receptor activity / myelin maintenance / Developmental Lineage of Multipotent Pancreatic Progenitor Cells ...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 / helper T cell enhancement of adaptive immune response / interleukin-16 binding / interleukin-16 receptor activity / myelin maintenance / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / C-X-C chemokine receptor activity / maintenance of protein location in cell / response to methamphetamine hydrochloride / cellular response to ionomycin / positive regulation of vasculature development / T cell selection / Signaling by ROBO receptors / MHC class II protein binding / Formation of definitive endoderm / C-C chemokine receptor activity / interleukin-15-mediated signaling pathway / cellular response to granulocyte macrophage colony-stimulating factor stimulus / C-C chemokine binding / positive regulation of monocyte differentiation / Alpha-defensins / Nef Mediated CD4 Down-regulation / anchoring junction / regulation of T cell activation / response to vitamin D / Chemokine receptors bind chemokines / dendritic cell chemotaxis / Other interleukin signaling / T cell receptor complex / extracellular matrix structural constituent / enzyme-linked receptor protein signaling pathway / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / cellular response to cytokine stimulus / cell leading edge / positive regulation of oligodendrocyte differentiation / Generation of second messenger molecules / macrophage differentiation / immunoglobulin binding / T cell differentiation / Co-inhibition by PD-1 / positive regulation of calcium ion transport into cytosol / Binding and entry of HIV virion / regulation of cell adhesion / positive regulation of interleukin-2 production / coreceptor activity / positive regulation of T cell proliferation / positive regulation of calcium-mediated signaling / neurogenesis / cell surface receptor protein tyrosine kinase signaling pathway / protein tyrosine kinase binding / cell chemotaxis / ubiquitin binding / Vpu mediated degradation of CD4 / calcium-mediated signaling / clathrin-coated endocytic vesicle membrane / brain development / G protein-coupled receptor activity / response to virus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / MHC class II protein complex binding / late endosome / transmembrane signaling receptor activity / response to estradiol / Downstream TCR signaling / Cargo recognition for clathrin-mediated endocytosis / T cell receptor signaling pathway / positive regulation of cold-induced thermogenesis / Clathrin-mediated endocytosis / virus receptor activity / positive regulation of cytosolic calcium ion concentration / signaling receptor activity / actin binding / cytoplasmic vesicle / G alpha (i) signalling events / defense response to Gram-negative bacterium / response to ethanol / adaptive immune response / early endosome / response to hypoxia / lysosome / cell surface receptor signaling pathway / cell adhesion / positive regulation of cell migration / immune response / membrane raft / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / inflammatory response / external side of plasma membrane / apoptotic process / ubiquitin protein ligase binding / symbiont entry into host cell / lipid binding / endoplasmic reticulum membrane / protein kinase binding
Similarity search - Function
CXC chemokine receptor 4 N-terminal domain / CXCR4 Chemokine receptor N terminal / CXC chemokine receptor 4/atypical chemokine receptor 2 / CD4, extracellular / T cell CD4 receptor C-terminal region / CD4, extracellular / T cell CD4 receptor C terminal region / T-cell surface antigen CD4 / Immunoglobulin C2-set / Immunoglobulin C2-set domain ...CXC chemokine receptor 4 N-terminal domain / CXCR4 Chemokine receptor N terminal / CXC chemokine receptor 4/atypical chemokine receptor 2 / CD4, extracellular / T cell CD4 receptor C-terminal region / CD4, extracellular / T cell CD4 receptor C terminal region / T-cell surface antigen CD4 / Immunoglobulin C2-set / Immunoglobulin C2-set domain / Chemokine receptor family / : / Immunoglobulin / Immunoglobulin domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Immunoglobulin V-Type / Immunoglobulin V-set domain / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / Immunoglobulin subtype / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
T-cell surface glycoprotein CD4 / C-X-C chemokine receptor type 4
Similarity search - Component
Biological speciesCronobacter phage ES2 (virus) / Homo sapiens (human) / Virus-associated RNAs
Methodsingle particle reconstruction / cryo EM / Resolution: 5.65 Å
AuthorsZhang Z / Patel DJ
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)P30CA008748 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 8, 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_48219.png

Downloads & links

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Map

FileDownload / File: emd_48219.map.gz / Format: CCP4 / Size: 282.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcryo-EM density map of CXCR4 bound to HIV-2/gp120-CD4 complex
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: 0.06
Minimum - Maximum-0.27825853 - 0.5591555
Average (Standard dev.)-0.000005426938 (±0.02060044)
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: cryo-EM half B density map of CXCR4 bound to HIV-2/gp120-CD4 complex.

Fileemd_48219_half_map_1.map
Annotationcryo-EM half B density map of CXCR4 bound to HIV-2/gp120-CD4 complex.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: cryo-EM half A density map of CXCR4 bound to HIV-2/gp120-CD4 complex

Fileemd_48219_half_map_2.map
Annotationcryo-EM half A density map of CXCR4 bound to HIV-2/gp120-CD4 complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : cryoEM structure of CXCR4-HIV-2/gp120-CD4 complex

EntireName: cryoEM structure of CXCR4-HIV-2/gp120-CD4 complex
Components
  • Complex: cryoEM structure of CXCR4-HIV-2/gp120-CD4 complex
    • Protein or peptide: C-X-C chemokine receptor type 4
    • Protein or peptide: T-cell surface glycoprotein CD4
    • Protein or peptide: HIV-1/gp120

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Supramolecule #1: cryoEM structure of CXCR4-HIV-2/gp120-CD4 complex

SupramoleculeName: cryoEM structure of CXCR4-HIV-2/gp120-CD4 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Cronobacter phage ES2 (virus)

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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: T-cell surface glycoprotein CD4

MacromoleculeName: T-cell surface glycoprotein CD4 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 19.541176 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
KKVVLGKKGD TVELTCTASQ KKSIQFHWKN SNQIKILGNQ GSFLTKGPSK LNDRADSRRS LWDQGNFPLI IKNLKIEDSD TYICEVEDQ KEEVQLLVFG LTANSDTHLL QGQSLTLTLE SPPGSSPSVQ CRSPRGKNIQ GGKTLSVSQL ELQDSGTWTC T VLQNQKKV EFKIDIVV

UniProtKB: T-cell surface glycoprotein CD4

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Macromolecule #3: HIV-1/gp120

MacromoleculeName: HIV-1/gp120 / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Virus-associated RNAs
Molecular weightTheoretical: 55.289422 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: KQFVTVFYGI PAWRNASIPL FCATKNRDTW GTIQCLPDND DYQEIALNVT EAFDAWNNTV TEQAVEDVWN LFETSIKPCV KLTPLCVAM NCTRNMTTST GTTDTQNITI INDTSPCVRA DNCTGLKEEE MVDCQFNMTG LERDKRKQYT EAWYSKDVIC D NNTSSRSK ...String:
KQFVTVFYGI PAWRNASIPL FCATKNRDTW GTIQCLPDND DYQEIALNVT EAFDAWNNTV TEQAVEDVWN LFETSIKPCV KLTPLCVAM NCTRNMTTST GTTDTQNITI INDTSPCVRA DNCTGLKEEE MVDCQFNMTG LERDKRKQYT EAWYSKDVIC D NNTSSRSK CYMNHCNTSV ITESCDKHYW DAMRFRYCAP PGFALLRCND TNYSGFAPNC SKVVAATCTR MMETQSSTWF GF NGTRAEN RTYIYWHGKN NRTIISLNNF YNLTMHCKRP GNKTVLPIMS GFKFHSKPVI NKKPRQAWCW FKGEWKEAMQ EVK ETLAKH PRYKGNRSRT ENIKFKAPGR GSDPEAAYMW TNCRGEFLYC NMTWFLNWVD NRTGQKQRNY APCHIRQIIN TWHR VGKNV YLPPREGELT CNSTVTSIIA NIDTGDQTDI TFSAEVAELY RLELGDYKLV EITPIGFAPT SVKRYSSAHQ RHTR

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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: 60.3 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: Alphaflod2
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.65 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 41735
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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