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- PDB-7xa3: Cryo-EM structure of the CCL2 bound CCR2-Gi complex -

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Basic information

Entry
Database: PDB / ID: 7xa3
TitleCryo-EM structure of the CCL2 bound CCR2-Gi complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • C-C motif chemokine 2
  • Isoform B of C-C chemokine receptor type 2
  • scFv16
KeywordsMEMBRANE PROTEIN / GPCR / CCR2 / Chemokine Receptor / MEMBRNE PROTEIN
Function / homology
Function and homology information


T-helper 17 cell chemotaxis / chemokine (C-C motif) ligand 2 binding / chemokine (C-C motif) ligand 12 binding / negative regulation of eosinophil degranulation / positive regulation of immune complex clearance by monocytes and macrophages / positive regulation of CD8-positive, alpha-beta T cell extravasation / positive regulation of astrocyte chemotaxis / leukocyte adhesion to vascular endothelial cell / chemokine (C-C motif) ligand 7 binding / positive regulation of thymocyte migration ...T-helper 17 cell chemotaxis / chemokine (C-C motif) ligand 2 binding / chemokine (C-C motif) ligand 12 binding / negative regulation of eosinophil degranulation / positive regulation of immune complex clearance by monocytes and macrophages / positive regulation of CD8-positive, alpha-beta T cell extravasation / positive regulation of astrocyte chemotaxis / leukocyte adhesion to vascular endothelial cell / chemokine (C-C motif) ligand 7 binding / positive regulation of thymocyte migration / positive regulation of hematopoietic stem cell migration / helper T cell extravasation / monocyte extravasation / regulation of vascular endothelial growth factor production / CCR2 chemokine receptor binding / negative regulation of type 2 immune response / negative regulation of natural killer cell chemotaxis / positive regulation of NMDA glutamate receptor activity / Beta defensins / macrophage migration / positive regulation of monocyte extravasation / regulation of macrophage migration / regulation of T cell cytokine production / chemokine receptor activity / neutrophil clearance / astrocyte cell migration / positive regulation of leukocyte tethering or rolling / inflammatory response to wounding / positive regulation of T-helper 1 type immune response / positive regulation of T cell chemotaxis / negative regulation of glial cell apoptotic process / positive regulation of alpha-beta T cell proliferation / ATF4 activates genes in response to endoplasmic reticulum stress / positive regulation of apoptotic cell clearance / CCR chemokine receptor binding / C-C chemokine receptor activity / C-C chemokine binding / negative regulation of adenylate cyclase activity / positive regulation of endothelial cell apoptotic process / NFE2L2 regulating inflammation associated genes / cellular homeostasis / eosinophil chemotaxis / positive regulation of monocyte chemotaxis / cellular response to fibroblast growth factor stimulus / chemokine-mediated signaling pathway / Chemokine receptors bind chemokines / chemokine activity / negative regulation of vascular endothelial cell proliferation / dendritic cell chemotaxis / regulation of T cell differentiation / negative regulation of G1/S transition of mitotic cell cycle / macrophage chemotaxis / positive regulation of calcium ion import / monocyte chemotaxis / positive regulation of nitric-oxide synthase biosynthetic process / Interleukin-10 signaling / cell surface receptor signaling pathway via JAK-STAT / hemopoiesis / humoral immune response / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / cellular response to interleukin-1 / blood vessel remodeling / T cell migration / D2 dopamine receptor binding / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / cellular defense response / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / homeostasis of number of cells within a tissue / cytoskeleton organization / sensory perception of pain / positive regulation of interleukin-2 production / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / negative regulation of angiogenesis / viral genome replication / positive regulation of synaptic transmission, glutamatergic / cell chemotaxis / Regulation of insulin secretion / G protein-coupled receptor binding / animal organ morphogenesis / response to bacterium / calcium-mediated signaling / 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 / cellular response to type II interferon / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / cytokine-mediated signaling pathway / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation
Similarity search - Function
CC chemokine receptor 2 / Chemokine receptor family / CC chemokine, conserved site / Small cytokines (intercrine/chemokine) C-C subfamily signature. / : / 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 ...CC chemokine receptor 2 / Chemokine receptor family / CC chemokine, conserved site / Small cytokines (intercrine/chemokine) C-C subfamily signature. / : / 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 / Serpentine type 7TM GPCR chemoreceptor Srsx / 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
C-C motif chemokine 2 / C-C chemokine receptor type 2 / 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: 2.9 Å
AuthorsShao, Z. / Tan, Y. / Shen, Q. / Yao, B. / Hou, L. / Qin, J. / Xu, P. / Mao, C. / Chen, L. / Zhang, H. ...Shao, Z. / Tan, Y. / Shen, Q. / Yao, B. / Hou, L. / Qin, J. / Xu, P. / Mao, C. / Chen, L. / Zhang, H. / Shen, D. / Zhang, C. / Li, W. / Du, X. / Li, F. / Chen, Z. / Jiang, Y. / Xu, H.E. / Ying, S. / Ma, H. / Zhang, Y. / Shen, H.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cell Discov / Year: 2022
Title: Molecular insights into ligand recognition and activation of chemokine receptors CCR2 and CCR3.
Authors: Zhehua Shao / Yangxia Tan / Qingya Shen / Li Hou / Bingpeng Yao / Jiao Qin / Peiyu Xu / Chunyou Mao / Li-Nan Chen / Huibing Zhang / Dan-Dan Shen / Chao Zhang / Weijie Li / Xufei Du / Fei Li ...Authors: Zhehua Shao / Yangxia Tan / Qingya Shen / Li Hou / Bingpeng Yao / Jiao Qin / Peiyu Xu / Chunyou Mao / Li-Nan Chen / Huibing Zhang / Dan-Dan Shen / Chao Zhang / Weijie Li / Xufei Du / Fei Li / Zhi-Hua Chen / Yi Jiang / H Eric Xu / Songmin Ying / Honglei Ma / Yan Zhang / Huahao Shen /
Abstract: Chemokine receptors are a family of G-protein-coupled receptors with key roles in leukocyte migration and inflammatory responses. Here, we present cryo-electron microscopy structures of two human CC ...Chemokine receptors are a family of G-protein-coupled receptors with key roles in leukocyte migration and inflammatory responses. Here, we present cryo-electron microscopy structures of two human CC chemokine receptor-G-protein complexes: CCR2 bound to its endogenous ligand CCL2, and CCR3 in the apo state. The structure of the CCL2-CCR2-G-protein complex reveals that CCL2 inserts deeply into the extracellular half of the transmembrane domain, and forms substantial interactions with the receptor through the most N-terminal glutamine. Extensive hydrophobic and polar interactions are present between both two chemokine receptors and the Gα-protein, contributing to the constitutive activity of these receptors. Notably, complemented with functional experiments, the interactions around intracellular loop 2 of the receptors are found to be conserved and play a more critical role in G-protein activation than those around intracellular loop 3. Together, our findings provide structural insights into chemokine recognition and receptor activation, shedding lights on drug design targeting chemokine receptors.
History
DepositionMar 17, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 24, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
R: Isoform B of C-C chemokine receptor type 2
L: C-C motif chemokine 2
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
E: scFv16


Theoretical massNumber of molelcules
Total (without water)164,2916
Polymers164,2916
Non-polymers00
Water00
1


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

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Components

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Protein , 2 types, 2 molecules RL

#1: Protein Isoform B of C-C chemokine receptor type 2 / C-C CKR-2 / CC-CKR-2 / CCR-2 / CCR2 / Monocyte chemoattractant protein 1 receptor / MCP-1-R


Mass: 41104.332 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCR2, CMKBR2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P41597
#2: Protein C-C motif chemokine 2 / HC11 / Monocyte chemoattractant protein 1 / Monocyte chemotactic and activating factor / MCAF / ...HC11 / Monocyte chemoattractant protein 1 / Monocyte chemotactic and activating factor / MCAF / Monocyte chemotactic protein 1 / MCP-1 / Monocyte secretory protein JE / Small-inducible cytokine A2


Mass: 7913.181 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCL2, MCP1, SCYA2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P13500

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABC

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


Mass: 40445.059 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Cell (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39597.230 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
#5: 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 / Cell (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Antibody , 1 types, 1 molecules E

#6: Antibody scFv16


Mass: 27370.510 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)

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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: Cryo-EM structure of the apo CCR3-Gi complex / Type: COMPLEX / Entity ID: all / 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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 62 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 142391 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0059824
ELECTRON MICROSCOPYf_angle_d0.84413298
ELECTRON MICROSCOPYf_dihedral_angle_d11.8325846
ELECTRON MICROSCOPYf_chiral_restr0.0521507
ELECTRON MICROSCOPYf_plane_restr0.0061682

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