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- EMDB-33108: Cryo-EM structure of the human chemokine receptor CX3CR1 in compl... -

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Basic information

Entry
Database: EMDB / ID: EMD-33108
TitleCryo-EM structure of the human chemokine receptor CX3CR1 in complex with CX3CL1 and Gi1
Map data
Sample
  • Complex: Chemokine receptor CX3CR1 in complex with CX3CL1 Gi1
    • 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: Processed fractalkine,CX3C chemokine receptor 1
  • Ligand: CHOLESTEROL
Function / homology
Function and homology information


C-X3-C chemokine receptor activity / dendritic tree / multiple spine synapse organization, single dendrite / negative regulation of microglial cell mediated cytotoxicity / regulation of microglial cell migration / CXCR1 chemokine receptor binding / positive regulation of calcium-independent cell-cell adhesion / negative regulation of glutamate receptor signaling pathway / negative regulation of interleukin-1 alpha production / leukocyte adhesive activation ...C-X3-C chemokine receptor activity / dendritic tree / multiple spine synapse organization, single dendrite / negative regulation of microglial cell mediated cytotoxicity / regulation of microglial cell migration / CXCR1 chemokine receptor binding / positive regulation of calcium-independent cell-cell adhesion / negative regulation of glutamate receptor signaling pathway / negative regulation of interleukin-1 alpha production / leukocyte adhesive activation / CX3C chemokine receptor binding / negative regulation of hippocampal neuron apoptotic process / C-X3-C chemokine binding / microglial cell activation involved in immune response / host-mediated regulation of intestinal microbiota composition / autocrine signaling / synapse pruning / negative regulation of neuron migration / central nervous system maturation / positive regulation of microglial cell migration / negative regulation of microglial cell activation / synapse maturation / antifungal innate immune response / regulation of lipopolysaccharide-mediated signaling pathway / positive regulation of transforming growth factor beta1 production / chemokine receptor activity / positive regulation of I-kappaB phosphorylation / microglial cell proliferation / CCR chemokine receptor binding / positive regulation of actin filament bundle assembly / lymphocyte chemotaxis / leukocyte migration involved in inflammatory response / leukocyte tethering or rolling / C-C chemokine receptor activity / integrin activation / C-C chemokine binding / angiogenesis involved in wound healing / regulation of tumor necrosis factor production / eosinophil chemotaxis / G protein-coupled peptide receptor activity / chemokine-mediated signaling pathway / positive regulation of monocyte chemotaxis / regulation of nitric oxide biosynthetic process / leukocyte chemotaxis / Chemokine receptors bind chemokines / chemokine activity / negative regulation of cell-substrate adhesion / negative regulation of interleukin-1 beta production / positive regulation of neurogenesis / positive regulation of cell-matrix adhesion / neuron remodeling / neuronal cell body membrane / positive regulation of neuroblast proliferation / positive chemotaxis / chemoattractant activity / plasma membrane => GO:0005886 / monocyte chemotaxis / negative regulation of interleukin-6 production / social behavior / negative regulation of apoptotic signaling pathway / negative regulation of tumor necrosis factor production / negative regulation of long-term synaptic potentiation / regulation of neurogenesis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / cellular response to interleukin-1 / D2 dopamine receptor binding / cellular defense response / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / extrinsic apoptotic signaling pathway in absence of ligand / cellular response to transforming growth factor beta stimulus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / negative regulation of cell migration / neutrophil chemotaxis / cell chemotaxis / positive regulation of release of sequestered calcium ion into cytosol / Regulation of insulin secretion / cell projection / G protein-coupled receptor activity / G protein-coupled receptor binding / response to ischemia / calcium-mediated signaling / positive regulation of smooth muscle cell proliferation / microglial cell activation / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / modulation of chemical synaptic transmission / regulation of synaptic plasticity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels
Similarity search - Function
CX3C chemokine receptor 1 / CX3C chemokine domain / 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 / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit ...CX3C chemokine receptor 1 / CX3C chemokine domain / 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 / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / 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
CX3C chemokine receptor 1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Fractalkine
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsLu M / Zhao W / Han S / Zhu Y / Wu B / Zhao Q
Funding support China, 3 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31825010 China
National Natural Science Foundation of China (NSFC)82121005 China
National Natural Science Foundation of China (NSFC)31800618 China
CitationJournal: Sci Adv / Year: 2022
Title: Activation of the human chemokine receptor CX3CR1 regulated by cholesterol.
Authors: Minmin Lu / Wenli Zhao / Shuo Han / Xiaowen Lin / Tingyu Xu / Qiuxiang Tan / Mu Wang / Cuiying Yi / Xiaojing Chu / Weibo Yang / Ya Zhu / Beili Wu / Qiang Zhao /
Abstract: As the only member of the CX3C chemokine receptor subfamily, CX3CR1 binds to its sole endogenous ligand CX3CL1, which shows notable potential as a therapeutic target in atherosclerosis, cancer, and ...As the only member of the CX3C chemokine receptor subfamily, CX3CR1 binds to its sole endogenous ligand CX3CL1, which shows notable potential as a therapeutic target in atherosclerosis, cancer, and neuropathy. However, the drug development of CX3CR1 is hampered partially by the lack of structural information. Here, we present two cryo-electron microscopy structures of CX3CR1-G complexes in ligand-free and CX3CL1-bound states at 2.8- and 3.4-Å resolution, respectively. Together with functional data, the structures reveal the key factors that govern the recognition of CX3CL1 by both CX3CR1 and US28. A much smaller conformational change of helix VI upon activation than previously solved class A GPCR-G complex structures is observed in CX3CR1, which may correlate with three cholesterol molecules that play essential roles in conformation stabilization and signaling transduction. Thus, our data deepen the understanding of cholesterol modulation in GPCR (G protein-coupled receptor) signaling and provide insights into the diversity of G protein coupling.
History
DepositionMar 22, 2022-
Header (metadata) releaseJul 13, 2022-
Map releaseJul 13, 2022-
UpdateJul 13, 2022-
Current statusJul 13, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33108.png

Downloads & links

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Map

FileDownload / File: emd_33108.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.045 Å
Density
Contour LevelBy AUTHOR: 0.018
Minimum - Maximum-0.104100116 - 0.1415014
Average (Standard dev.)8.8872713e-07 (±0.0027858668)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 267.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_33108_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_33108_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : Chemokine receptor CX3CR1 in complex with CX3CL1 Gi1

EntireName: Chemokine receptor CX3CR1 in complex with CX3CL1 Gi1
Components
  • Complex: Chemokine receptor CX3CR1 in complex with CX3CL1 Gi1
    • 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: Processed fractalkine,CX3C chemokine receptor 1
  • Ligand: CHOLESTEROL

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Supramolecule #1: Chemokine receptor CX3CR1 in complex with CX3CL1 Gi1

SupramoleculeName: Chemokine receptor CX3CR1 in complex with CX3CL1 Gi1 / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)

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

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.447141 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKCTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKCTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVTAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHASM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF

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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: 38.245805 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: HHHHHHMSEL DQLRQEAEQL KNQIRDARKA CADATLSQIT NNIDPVGRIQ MRTRRTLRGH LAKIYAMHWG TDSRLLVSAS QDGKLIIWD SYTTNKVHAI PLRSSWVMTC AYAPSGNYVA CGGLDNICSI YNLKTREGNV RVSRELAGHT GYLSCCRFLD D NQIVTSSG ...String:
HHHHHHMSEL DQLRQEAEQL KNQIRDARKA CADATLSQIT NNIDPVGRIQ MRTRRTLRGH LAKIYAMHWG TDSRLLVSAS QDGKLIIWD SYTTNKVHAI PLRSSWVMTC AYAPSGNYVA CGGLDNICSI YNLKTREGNV RVSRELAGHT GYLSCCRFLD D NQIVTSSG DTTCALWDIE TGQQTTTFTG HTGDVMSLSL APDTRLFVSG ACDASAKLWD VREGMCRQTF TGHESDINAI CF FPNGNAF ATGSDDATCR LFDLRADQEL MTYSHDNIIC GITSVSFSKS GRLLLAGYDD FNCNVWDALK ADRAGVLAGH DNR VSCLGV TDDGMAVATG SWDSFLKIWN

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Macromolecule #3: 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: 3 / 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

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Macromolecule #4: Processed fractalkine,CX3C chemokine receptor 1

MacromoleculeName: Processed fractalkine,CX3C chemokine receptor 1 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 51.55825 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: (PCA)HHGVTKCNI TCSKMTSKIP VALLIHYQQN QASCCKRAII LETRQHRLFC ADPKEQWVKD AMQHLDRQAA ALTRNG SGS GSGSGSGSGS GSGSGSGSGS GSGSDQFPES VTENFEYDDL AEACYIGDIV VFGTVFLSIF YSVIFAIGLV GNLLVVF AL TNSKKPKSVT ...String:
(PCA)HHGVTKCNI TCSKMTSKIP VALLIHYQQN QASCCKRAII LETRQHRLFC ADPKEQWVKD AMQHLDRQAA ALTRNG SGS GSGSGSGSGS GSGSGSGSGS GSGSDQFPES VTENFEYDDL AEACYIGDIV VFGTVFLSIF YSVIFAIGLV GNLLVVF AL TNSKKPKSVT DIYLLNLALS DLLFVATLPF WTHYLINEKG LHNAMCKFTT AFFFIGFFGS IFFLTVISID RYLAIVLA A NSMNNRTVQH GVTISLGVWA AAILVAAPQF MFTKQKENEC CGDYPEVLQE IWPVLRNVET NFLGFLLPLL IMSYCYFRI IQTLFSSKNH KKAKAIKLIL LVVIVFFLFW TPYNVVIFLE TLKLYDFFPS CDMRKDLRLA LSVTETVAFS HCCLNPLIYA FAGEKFRRY LYHLYGKCLA VLEFLEVLFQ GPWSHPQFEK GGGSGGGSGG SAWSHPQFEK DYKDDDDK

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Macromolecule #5: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 2 / 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

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 2.1875 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 490779
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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