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- EMDB-36869: Cryo-EM structure of CXCR4 in complex with CXCL12 -

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Entry
Database: EMDB / ID: EMD-36869
TitleCryo-EM structure of CXCR4 in complex with CXCL12
Map data
Sample
  • Complex: CXCR4-CXCL12-Gi-scFv16 complex
    • Protein or peptide: scFv16
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: C-X-C chemokine receptor type 4
    • Protein or peptide: Stromal cell-derived factor 1
KeywordsChemokine receptor / CXCR4 / IMMUNE SYSTEM
Function / homology
Function and homology information


C-X-C motif chemokine 12 receptor activity / regulation of viral process / chemokine (C-X-C motif) ligand 12 signaling pathway / negative regulation of leukocyte tethering or rolling / positive regulation of vascular wound healing / positive regulation of macrophage migration inhibitory factor signaling pathway / neuron recognition / regulation of actin polymerization or depolymerization / telencephalon cell migration / positive regulation of mesenchymal stem cell migration ...C-X-C motif chemokine 12 receptor activity / regulation of viral process / chemokine (C-X-C motif) ligand 12 signaling pathway / negative regulation of leukocyte tethering or rolling / positive regulation of vascular wound healing / positive regulation of macrophage migration inhibitory factor signaling pathway / neuron recognition / regulation of actin polymerization or depolymerization / telencephalon cell migration / positive regulation of mesenchymal stem cell migration / chemokine receptor binding / 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 axon extension involved in axon guidance / positive regulation of vasculature development / CXCR chemokine receptor binding / endothelial tube morphogenesis / positive regulation of dopamine secretion / endothelial cell differentiation / Signaling by ROBO receptors / regulation of chemotaxis / positive regulation of dendrite extension / induction of positive chemotaxis / Formation of definitive endoderm / positive regulation of chemotaxis / integrin activation / C-C chemokine receptor activity / negative regulation of dendritic cell apoptotic process / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / cellular response to chemokine / C-C chemokine binding / positive regulation of monocyte chemotaxis / chemokine-mediated signaling pathway / chemokine activity / blood circulation / Chemokine receptors bind chemokines / anchoring junction / dendritic cell chemotaxis / epithelial cell development / cellular response to cytokine stimulus / positive regulation of calcium ion import / cell leading edge / small molecule binding / detection of temperature stimulus involved in sensory perception of pain / regulation of calcium ion transport / positive regulation of oligodendrocyte differentiation / positive regulation of T cell migration / Binding and entry of HIV virion / animal organ regeneration / regulation of cell adhesion / detection of mechanical stimulus involved in sensory perception of pain / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / Nuclear signaling by ERBB4 / T cell migration / coreceptor activity / cardiac muscle contraction / D2 dopamine receptor binding / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / adenylate cyclase regulator activity / positive regulation of endothelial cell proliferation / regulation of mitotic spindle organization / cellular response to forskolin / positive regulation of cell adhesion / positive regulation of neuron differentiation / axon guidance / adult locomotory behavior / ubiquitin binding / response to activity / neurogenesis / cell chemotaxis / Regulation of insulin secretion / growth factor activity / G protein-coupled receptor binding / calcium-mediated signaling / neuron migration / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor activity / defense response / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / brain development / response to virus / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / response to peptide hormone / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation
Similarity search - Function
CXC chemokine receptor 4 N-terminal domain / CXCR4 Chemokine receptor N terminal / CXC chemokine receptor 4/atypical chemokine receptor 2 / CXC Chemokine domain / Chemokine receptor family / : / Chemokine beta/gamma/delta / Intercrine alpha family (small cytokine C-X-C) (chemokine CXC). / Chemokine interleukin-8-like domain / Chemokine interleukin-8-like superfamily ...CXC chemokine receptor 4 N-terminal domain / CXCR4 Chemokine receptor N terminal / CXC chemokine receptor 4/atypical chemokine receptor 2 / CXC Chemokine domain / Chemokine receptor family / : / Chemokine beta/gamma/delta / Intercrine alpha family (small cytokine C-X-C) (chemokine CXC). / Chemokine interleukin-8-like domain / Chemokine interleukin-8-like superfamily / Small cytokines (intecrine/chemokine), interleukin-8 like / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Stromal cell-derived factor 1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / C-X-C chemokine receptor type 4 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human) / Vicugna pacos (alpaca)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.81 Å
AuthorsLiu YZ / Liu AJ / Liao QW / Ye RD
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cell Rep / Year: 2024
Title: Cryo-EM structure of monomeric CXCL12-bound CXCR4 in the active state.
Authors: Yezhou Liu / Aijun Liu / Xinyu Li / Qiwen Liao / Weijia Zhang / Lizhe Zhu / Richard D Ye /
Abstract: CXCR4 binding of its endogenous agonist CXCL12 leads to diverse functions, including bone marrow retention of hematopoietic progenitors and cancer metastasis. However, the structure of the CXCL12- ...CXCR4 binding of its endogenous agonist CXCL12 leads to diverse functions, including bone marrow retention of hematopoietic progenitors and cancer metastasis. However, the structure of the CXCL12-bound CXCR4 remains unresolved despite available structures of CXCR4 in complex with antagonists. Here, we present the cryoelectron microscopy (cryo-EM) structure of the CXCL12-CXCR4-Gi complex at an overall resolution of 2.65 Å. CXCL12 forms a 1:1 stoichiometry complex with CXCR4, following the two-site model. The first 8 amino acids of mature CXCL12 are crucial for CXCR4 activation by forming polar interactions with minor sub-pocket residues in the transmembrane binding pocket. The 3.2-Å distance between V3 of CXCL12 and the "toggle switch" W marks the deepest insertion among all chemokine-receptor pairs, leading to conformational changes of CXCR4 for G protein activation. These results, combined with functional assays and computational analysis, provide the structural basis for CXCR4 activation by CXCL12.
History
DepositionJul 17, 2023-
Header (metadata) releaseJul 17, 2024-
Map releaseJul 17, 2024-
UpdateJan 29, 2025-
Current statusJan 29, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36869.png

Downloads & links

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Map

FileDownload / File: emd_36869.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
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: 0.4
Minimum - Maximum-4.273621 - 6.095197
Average (Standard dev.)-0.0026178018 (±0.13105038)
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: #1

Fileemd_36869_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_36869_half_map_2.map
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Sample components

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Entire : CXCR4-CXCL12-Gi-scFv16 complex

EntireName: CXCR4-CXCL12-Gi-scFv16 complex
Components
  • Complex: CXCR4-CXCL12-Gi-scFv16 complex
    • Protein or peptide: scFv16
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: C-X-C chemokine receptor type 4
    • Protein or peptide: Stromal cell-derived factor 1

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Supramolecule #1: CXCR4-CXCL12-Gi-scFv16 complex

SupramoleculeName: CXCR4-CXCL12-Gi-scFv16 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #6, #5, #2-#3, #1, #4
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: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 33.826059 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: KEPCFREENA NFNKIFLPTI YSIIFLTGIV GNGLVILVMG YQKKLRSMTD KYRLHLSVAD LLFVITLPFW AVDAVANWYF GNFLCKAVH VIYTVNLYSS VLILAFISLD RYLAIVHATN SQRPRKLLAE KVVYVGVWIP ALLLTIPDFI FANVSEADDR Y ICDRFYPN ...String:
KEPCFREENA NFNKIFLPTI YSIIFLTGIV GNGLVILVMG YQKKLRSMTD KYRLHLSVAD LLFVITLPFW AVDAVANWYF GNFLCKAVH VIYTVNLYSS VLILAFISLD RYLAIVHATN SQRPRKLLAE KVVYVGVWIP ALLLTIPDFI FANVSEADDR Y ICDRFYPN DLWVVVFQFQ HIMVGLILPG IVILSCYCII ISKLSHSKGH QKRKALKTTV ILILAFFACW LPYYIGISID SF ILLEIIK QGCEFENTVH KWISITEALA FFHCCLNPIL YAFLGAKFKT SAQHALTSV

UniProtKB: C-X-C chemokine receptor type 4

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.198656 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLVS ASQDGKLIIW DSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG HTGYLSCCRF LDDNQIVTSS G DTTCALWD ...String:
ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLVS ASQDGKLIIW DSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG HTGYLSCCRF LDDNQIVTSS G DTTCALWD IETGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TFTGHESDIN AICFFPNGNA FA TGSDDAT CRLFDLRADQ ELMTYSHDNI ICGITSVSFS KSGRLLLAGY DDFNCNVWDA LKADRAGVLA GHDNRVSCLG VTD DGMAVA TGSWDSFLKI WN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.415031 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGGQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCA TDTKNVQFVF DAVTDVIIKN NLKDCGLF

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1

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Macromolecule #4: Stromal cell-derived factor 1

MacromoleculeName: Stromal cell-derived factor 1 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.292648 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
KPVSLSYRCP CRFFESHVAR ANVKHLKILN TPNCALQIVA RLKNNNRQVC IDPKLKWIQE YL

UniProtKB: Stromal cell-derived factor 1

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Macromolecule #5: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 6.131084 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
IAQARKLVEQ LKMEANIDRI KVSKAAADLM AYCEAHAKED PLLTPVPASE NPFRE

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #6: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Vicugna pacos (alpaca)
Molecular weightTheoretical: 26.337307 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL

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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
GridMaterial: GOLD
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: 50.0 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: 1.0 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: 2.81 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 373108
Initial angle assignmentType: COMMON LINE
Final angle assignmentType: COMMON LINE
FSC plot (resolution estimation)

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