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- PDB-7vl9: Cryo-EM structure of the CCL15(26-92) bound CCR1-Gi complex -

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Basic information

Entry
Database: PDB / ID: 7vl9
TitleCryo-EM structure of the CCL15(26-92) bound CCR1-Gi complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • C-C chemokine receptor type 1
  • CCL15(26-92)
  • scFv16
KeywordsMEMBRANE PROTEIN / GPCR / CCR1 / Chemokine Receptor / MEMBRNE PROTEIN
Function / homology
Function and homology information


chemokine (C-C motif) ligand 7 binding / chemokine (C-C motif) ligand 5 binding / chemokine receptor activity / CCR chemokine receptor binding / phosphatidylinositol-4,5-bisphosphate phospholipase C activity / negative regulation of bone mineralization / C-C chemokine binding / C-C chemokine receptor activity / positive regulation of calcium ion transport / positive regulation of osteoclast differentiation ...chemokine (C-C motif) ligand 7 binding / chemokine (C-C motif) ligand 5 binding / chemokine receptor activity / CCR chemokine receptor binding / phosphatidylinositol-4,5-bisphosphate phospholipase C activity / negative regulation of bone mineralization / C-C chemokine binding / C-C chemokine receptor activity / positive regulation of calcium ion transport / positive regulation of osteoclast differentiation / positive regulation of monocyte chemotaxis / chemokine activity / Chemokine receptors bind chemokines / positive regulation of neuroinflammatory response / dendritic cell chemotaxis / chemoattractant activity / Interleukin-10 signaling / exocytosis / monocyte chemotaxis / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / chemokine-mediated signaling pathway / cell chemotaxis / calcium-mediated signaling / Regulation of insulin secretion / neuropeptide signaling pathway / response to prostaglandin E / positive regulation of cholesterol biosynthetic process / response to wounding / negative regulation of insulin secretion / G protein-coupled receptor binding / response to peptide hormone / chemotaxis / intracellular calcium ion homeostasis / centriolar satellite / cytokine-mediated signaling pathway / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / positive regulation of inflammatory response / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / calcium ion transport / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / G beta:gamma signalling through BTK / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / GDP binding / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cell-cell signaling / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / antimicrobial humoral immune response mediated by antimicrobial peptide / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / heparin binding / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / extracellular vesicle / sensory perception of taste / Thrombin signalling through proteinase activated receptors (PARs) / sperm principal piece / adenylate cyclase-activating G protein-coupled receptor signaling pathway / signaling receptor complex adaptor activity / positive regulation of cytosolic calcium ion concentration / retina development in camera-type eye / fibroblast proliferation / GTPase binding / G protein activity / midbody
Similarity search - Function
CC chemokine receptor 1 / CC chemokine, conserved site / Small cytokines (intercrine/chemokine) C-C subfamily signature. / 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 / : ...CC chemokine receptor 1 / CC chemokine, conserved site / Small cytokines (intercrine/chemokine) C-C subfamily signature. / 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 / : / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / YVTN repeat-like/Quinoprotein amine dehydrogenase / G-protein alpha subunit, group I / 7 Propeller / Methylamine Dehydrogenase; Chain H / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / 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 / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 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. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Immunoglobulins / Up-down Bundle / Immunoglobulin-like / Sandwich / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
CHOLESTEROL / C-C chemokine receptor type 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 / C-C motif chemokine 15
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsShao, Z. / Shen, Q. / Mao, C. / Yao, B. / Chen, L. / Zhang, H. / Shen, D. / Zhang, C. / Li, W. / Du, X. ...Shao, Z. / Shen, Q. / Mao, C. / Yao, B. / Chen, L. / Zhang, H. / Shen, D. / Zhang, C. / Li, W. / Du, X. / Li, F. / Ma, H. / Chen, Z. / Xu, H.E. / Ying, S. / Zhang, Y. / Shen, H.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Chem Biol / Year: 2022
Title: Identification and mechanism of G protein-biased ligands for chemokine receptor CCR1.
Authors: Zhehua Shao / Qingya Shen / Bingpeng Yao / Chunyou Mao / Li-Nan Chen / Huibing Zhang / Dan-Dan Shen / Chao Zhang / Weijie Li / Xufei Du / Fei Li / Honglei Ma / Zhi-Hua Chen / H Eric Xu / ...Authors: Zhehua Shao / Qingya Shen / Bingpeng Yao / Chunyou Mao / Li-Nan Chen / Huibing Zhang / Dan-Dan Shen / Chao Zhang / Weijie Li / Xufei Du / Fei Li / Honglei Ma / Zhi-Hua Chen / H Eric Xu / Songmin Ying / Yan Zhang / Huahao Shen /
Abstract: Biased signaling of G protein-coupled receptors describes an ability of different ligands that preferentially activate an alternative downstream signaling pathway. In this work, we identified and ...Biased signaling of G protein-coupled receptors describes an ability of different ligands that preferentially activate an alternative downstream signaling pathway. In this work, we identified and characterized different N-terminal truncations of endogenous chemokine CCL15 as balanced or biased agonists targeting CCR1, and presented three cryogenic-electron microscopy structures of the CCR1-G complex in the ligand-free form or bound to different CCL15 truncations with a resolution of 2.6-2.9 Å, illustrating the structural basis of natural biased signaling that initiates an inflammation response. Complemented with pharmacological and computational studies, these structures revealed it was the conformational change of Tyr291 (Y291) in CCR1 that triggered its polar network rearrangement in the orthosteric binding pocket and allosterically regulated the activation of β-arrestin signaling. Our structure of CCL15-bound CCR1 also exhibited a critical site for ligand binding distinct from many other chemokine-receptor complexes, providing new insights into the mode of chemokine recognition.
History
DepositionOct 2, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 23, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Data collection / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
L: CCL15(26-92)
R: C-C chemokine receptor type 1
S: scFv16
hetero molecules


Theoretical massNumber of molelcules
Total (without water)164,3007
Polymers163,9136
Non-polymers3871
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area14900 Å2
ΔGint-92 kcal/mol
Surface area52040 Å2

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Components

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

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


Mass: 40414.047 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
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37728.152 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

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Protein , 2 types, 2 molecules LR

#4: Protein CCL15(26-92)


Mass: 8365.681 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCL15, MIP5, NCC3, SCYA15 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q16663
#5: Protein C-C chemokine receptor type 1 / C-C CKR-1 / CC-CKR-1 / CCR-1 / CCR1 / HM145 / LD78 receptor / Macrophage inflammatory protein 1- ...C-C CKR-1 / CC-CKR-1 / CCR-1 / CCR1 / HM145 / LD78 receptor / Macrophage inflammatory protein 1-alpha receptor / MIP-1alpha-R / RANTES-R


Mass: 42203.547 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCR1, CMKBR1, CMKR1, SCYAR1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P32246

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Antibody / Non-polymers , 2 types, 2 molecules S

#6: Antibody scFv16


Mass: 27340.482 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)
#7: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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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: CCL15(26-92)-bound CCR1-Gi complex / Type: COMPLEX / Entity ID: #1-#6 / 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
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen 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
Image recordingElectron dose: 62 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 (6k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.18_3845refinement
PHENIX1.18_3845refinement
EM software
IDNameVersionCategory
4Gctfv1.18CTF correction
7Coot0.9model fitting
9PHENIX1.18model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 109180 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 6DO1

6do1


Accession code: 6DO1 / Source name: PDB / Type: experimental model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 46.52 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00669817
ELECTRON MICROSCOPYf_angle_d0.936713290
ELECTRON MICROSCOPYf_chiral_restr0.06241501
ELECTRON MICROSCOPYf_plane_restr0.00551667
ELECTRON MICROSCOPYf_dihedral_angle_d14.32623534

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