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- PDB-7xbw: Cryo-EM structure of the human chemokine receptor CX3CR1 in compl... -

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Basic information

Entry
Database: PDB / ID: 7xbw
TitleCryo-EM structure of the human chemokine receptor CX3CR1 in complex with Gi1
Components
  • 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
KeywordsSIGNALING PROTEIN / G protein-coupled receptor / chemokine receptor / CX3CR1
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 / 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 ...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 / 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 / central nervous system maturation / positive regulation of microglial cell migration / synapse maturation / antifungal innate immune response / chemokine receptor activity / positive regulation of I-kappaB phosphorylation / leukocyte tethering or rolling / C-C chemokine receptor activity / C-C chemokine binding / regulation of tumor necrosis factor production / G protein-coupled peptide receptor activity / positive regulation of monocyte chemotaxis / leukocyte chemotaxis / regulation of nitric oxide biosynthetic process / Chemokine receptors bind chemokines / negative regulation of interleukin-1 beta production / positive regulation of neurogenesis / neuronal cell body membrane / positive regulation of neuroblast proliferation / plasma membrane => GO:0005886 / social behavior / negative regulation of apoptotic signaling pathway / negative regulation of long-term synaptic potentiation / regulation of neurogenesis / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / cellular defense response / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / cellular response to transforming growth factor beta stimulus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / negative regulation of cell migration / cell chemotaxis / Regulation of insulin secretion / response to ischemia / G protein-coupled receptor binding / G protein-coupled receptor activity / calcium-mediated signaling / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / modulation of chemical synaptic transmission / regulation of synaptic plasticity / Activation of the phototransduction cascade / 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 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / brain development / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / memory / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / response to peptide hormone / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / response to wounding / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / positive regulation of angiogenesis / GPER1 signaling / GDP binding / chemotaxis / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle
Similarity search - Function
CX3C chemokine receptor 1 / 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 ...CX3C chemokine receptor 1 / 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
CHOLESTEROL / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsLu, M. / Zhao, W. / Han, S. / Zhu, Y. / Wu, B. / Zhao, Q.
Funding support China, 3items
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, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 13, 2022Provider: repository / Type: Initial release

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Structure visualization

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MolmilJmol/JSmol

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Assembly

Deposited unit
C: Guanine nucleotide-binding protein G(i) subunit alpha-1
D: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
E: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
R: CX3C chemokine receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,7877
Polymers127,6274
Non-polymers1,1603
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40447.141 Da / Num. of mol.: 1 / Mutation: S47C,G202T,G203A,E245A,A326S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38245.805 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768
#4: Protein CX3C chemokine receptor 1 / C-X3-C CKR-1 / CX3CR1 / Beta chemokine receptor-like 1 / CMK-BRL-1 / CMK-BRL1 / Fractalkine ...C-X3-C CKR-1 / CX3CR1 / Beta chemokine receptor-like 1 / CMK-BRL-1 / CMK-BRL1 / Fractalkine receptor / G-protein coupled receptor 13 / V28


Mass: 41072.680 Da / Num. of mol.: 1 / Mutation: I120L, C221S, M250V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CX3CR1, CMKBRL1, GPR13 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P49238
#5: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H46O
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Chemokine receptor CX3CR1 in complex with Gi1 / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 2.1875 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.18.2_3874refinement
PHENIX1.18.2_3874refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 702722 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 52.17 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00226810
ELECTRON MICROSCOPYf_angle_d0.45389312
ELECTRON MICROSCOPYf_chiral_restr0.03851130
ELECTRON MICROSCOPYf_plane_restr0.0041155
ELECTRON MICROSCOPYf_dihedral_angle_d4.1616951

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