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- EMDB-41889: Structure of CXCL12-bound CXCR4/Gi complex -

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Basic information

Entry
Database: EMDB / ID: EMD-41889
TitleStructure of CXCL12-bound CXCR4/Gi complex
Map data
Sample
  • Complex: CXCL12-bound CXCR4/Gi complex
    • Protein or peptide: C-X-C chemokine receptor type 4
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • 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)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Stromal cell-derived factor 1
  • Ligand: CHOLESTEROL
KeywordsGPCR / chemokine receptor / chemokine / SIGNALING PROTEIN
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 / positive regulation of mesenchymal stem cell migration / neuron recognition / response to ultrasound / telencephalon 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 / positive regulation of mesenchymal stem cell migration / neuron recognition / response to ultrasound / telencephalon cell migration / regulation of actin polymerization or depolymerization / C-X-C chemokine receptor activity / response to tacrolimus / Specification of primordial germ cells / CXCL12-activated CXCR4 signaling pathway / chemokine receptor binding / myosin light chain binding / myelin maintenance / positive regulation of vasculature development / regulation of programmed cell death / CXCR chemokine receptor binding / positive regulation of axon extension involved in axon guidance / positive regulation of dopamine secretion / endothelial tube morphogenesis / C-C chemokine receptor activity / endothelial cell differentiation / Signaling by ROBO receptors / regulation of chemotaxis / : / C-C chemokine binding / induction of positive chemotaxis / positive regulation of dendrite extension / positive regulation of chemotaxis / Formation of definitive endoderm / integrin activation / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / negative regulation of dendritic cell apoptotic process / cellular response to chemokine / positive regulation of monocyte chemotaxis / chemokine-mediated signaling pathway / Chemokine receptors bind chemokines / chemokine activity / blood circulation / anchoring junction / dendritic cell chemotaxis / positive regulation of oligodendrocyte differentiation / small molecule binding / epithelial cell development / positive regulation of calcium ion import / cell leading edge / cellular response to cytokine stimulus / detection of temperature stimulus involved in sensory perception of pain / regulation of calcium ion transport / T cell migration / detection of mechanical stimulus involved in sensory perception of pain / animal organ regeneration / positive regulation of T cell migration / D2 dopamine receptor binding / Binding and entry of HIV virion / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cell adhesion / regulation of cAMP-mediated signaling / coreceptor activity / G protein-coupled serotonin receptor binding / cardiac muscle contraction / cellular response to forskolin / Nuclear signaling by ERBB4 / regulation of mitotic spindle organization / positive regulation of endothelial cell proliferation / positive regulation of neuron differentiation / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / positive regulation of cell adhesion / neurogenesis / cell chemotaxis / adult locomotory behavior / ubiquitin binding / axon guidance / response to activity / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / calcium-mediated signaling / growth factor activity / neuron migration / brain development / response to virus / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / 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 / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.29 Å
AuthorsSaotome K / McGoldrick LL / Franklin MC
Funding support United States, 1 items
OrganizationGrant numberCountry
Not funded United States
Citation
Journal: Nat Struct Mol Biol / Year: 2024
Title: Structural insights into CXCR4 modulation and oligomerization.
Authors: Kei Saotome / Luke L McGoldrick / Jo-Hao Ho / Trudy F Ramlall / Sweta Shah / Michael J Moore / Jee Hae Kim / Raymond Leidich / William C Olson / Matthew C Franklin /
Abstract: Activation of the chemokine receptor CXCR4 by its chemokine ligand CXCL12 regulates diverse cellular processes. Previously reported crystal structures of CXCR4 revealed the architecture of an ...Activation of the chemokine receptor CXCR4 by its chemokine ligand CXCL12 regulates diverse cellular processes. Previously reported crystal structures of CXCR4 revealed the architecture of an inactive, homodimeric receptor. However, many structural aspects of CXCR4 remain poorly understood. Here, we use cryo-electron microscopy to investigate various modes of human CXCR4 regulation. CXCL12 activates CXCR4 by inserting its N terminus deep into the CXCR4 orthosteric pocket. The binding of US Food and Drug Administration-approved antagonist AMD3100 is stabilized by electrostatic interactions with acidic residues in the seven-transmembrane-helix bundle. A potent antibody blocker, REGN7663, binds across the extracellular face of CXCR4 and inserts its complementarity-determining region H3 loop into the orthosteric pocket. Trimeric and tetrameric structures of CXCR4 reveal modes of G-protein-coupled receptor oligomerization. We show that CXCR4 adopts distinct subunit conformations in trimeric and tetrameric assemblies, highlighting how oligomerization could allosterically regulate chemokine receptor function.
#1: Journal: Biorxiv / Year: 2024
Title: Structural insights into CXCR4 modulation and oligomerization
Authors: Saotome K / McGoldrick LL / Ho J / Ramlall T / Shah S / Moore MJ / Kim JH / Leidich R / Olson WC / Franklin MC
History
DepositionSep 11, 2023-
Header (metadata) releaseMar 13, 2024-
Map releaseMar 13, 2024-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41889.png

Downloads & links

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Map

FileDownload / File: emd_41889.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 300 pix.
= 255. Å		0.85 Å/pix.
x 300 pix.
= 255. Å		0.85 Å/pix.
x 300 pix.
= 255. Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-1.1792055 - 1.6499308
Average (Standard dev.)-0.00081704167 (±0.03753982)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 255.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_41889_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_41889_half_map_2.map
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Histogram (log scale)

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Sample components

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Entire : CXCL12-bound CXCR4/Gi complex

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

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Supramolecule #1: CXCL12-bound CXCR4/Gi complex

SupramoleculeName: CXCL12-bound CXCR4/Gi complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
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: 71.063609 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFAGAPE GISIYTSDNY TEEMGSGDYD SMKEPCFREE NANFNKIFLP TIYSIIFLTG IVGNGLVILV MGYQKKLRS MTDKYRLHLS VADLLFVITL PFWAVDAVAN WYFGNFLCKA VHVIYTVSLY SSVLILAFIS LDRYLAIVHA T NSQRPRKL ...String:
MKTIIALSYI FCLVFAGAPE GISIYTSDNY TEEMGSGDYD SMKEPCFREE NANFNKIFLP TIYSIIFLTG IVGNGLVILV MGYQKKLRS MTDKYRLHLS VADLLFVITL PFWAVDAVAN WYFGNFLCKA VHVIYTVSLY SSVLILAFIS LDRYLAIVHA T NSQRPRKL LAEKVVYVGV WIPALLLTIP DFIFANVSEA DDRYICDRFY PNDLWVVVFQ FQHIMVGLIL PGIVILSCYC II ISKLSHS KGHQKRKALK TTVILILAFF ACWLPYYIGI SIDSFILLEI IKQGCEFENT VHKWISITEA LAFFHCCLNP ILY AFLGAK FKTSAQHALT SVSRGSSLKI LSKGKRGGHS SVSTESESSS FHSSGRPLEV LFQGPGGGGS VSKGEELFTG VVPI LVELD GDVNGHKFSV SGEGEGDATY GKLTLKFICT TGKLPVPWPT LVTTLTYGVQ CFSRYPDHMK QHDFFKSAMP EGYVQ ERTI FFKDDGNYKT RAEVKFEGDT LVNRIELKGI DFKEDGNILG HKLEYNYNSH NVYIMADKQK NGIKVNFKIR HNIEDG SVQ LADHYQQNTP IGDGPVLLPD NHYLSTQSKL SKDPNEKRDH MVLLEFVTAA GITLGMDELY KDYKDDDDK

UniProtKB: C-X-C chemokine receptor type 4

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Macromolecule #2: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.591312 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHGGG GSGCTLSAED KAAVERSKMI DRNLREDGEK AAREVKLLLL GAGESGKCTI VKQMKIIHEA GYSEEECKQY KAVVYSNTI QSIIAIIRAM GRLKIDFGDS ARADDARQLF VLAGAAEEGF MTAELAGVIK RLWKDSGVQA CFNRSREYQL N DSAAYYLN ...String:
MHHHHHHGGG GSGCTLSAED KAAVERSKMI DRNLREDGEK AAREVKLLLL GAGESGKCTI VKQMKIIHEA GYSEEECKQY KAVVYSNTI QSIIAIIRAM GRLKIDFGDS ARADDARQLF VLAGAAEEGF MTAELAGVIK RLWKDSGVQA CFNRSREYQL N DSAAYYLN DLDRIAQPNY IPTQQDVLRT RVKTTGIVET HFTFKDLHFK MFDVTAQRSE RKKWIHCFEG VTAIIFCVAL SD YDLVLAE DEEMNRMHAS MKLFDSICNN KWFTDTSIIL FLNKKDLFEE KIKKSPLTIC YPEYAGSNTY EEAAAYIQCQ FED LNKRKD TKEIYTHFTC STDTKNVQFV FDAVTDVIIK NNLKDCGLF

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

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Macromolecule #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.534062 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHGSS GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKL IIWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC R FLDDNQIV ...String:
MHHHHHHGSS GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKL IIWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC R FLDDNQIV TSSGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD IN AICFFPN GNAFATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAG HDNRVS CLGVTDDGMA VATGSWDSFL KIWN

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

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Macromolecule #4: 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: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

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

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Macromolecule #5: Stromal cell-derived factor 1

MacromoleculeName: Stromal cell-derived factor 1 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.97846 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
KPVSLSYRCP CRFFESHVAR ANVKHLKILN TPNCALQIVA RLKNNNRQVC IDPKLKWIQE YLEKALNK

UniProtKB: Stromal cell-derived factor 1

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Macromolecule #6: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 6 / Number of copies: 1 / 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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 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: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.29 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 87963
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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