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- PDB-8ic0: Cryo-EM structure of CXCL8 bound C-X-C chemokine receptor 1 in co... -

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Basic information

Entry
Database: PDB / ID: 8ic0
TitleCryo-EM structure of CXCL8 bound C-X-C chemokine receptor 1 in complex with Gi heterotrimer
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • C-X-C chemokine receptor type 1
  • Interleukin-8
  • scFv16
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / GPCR / Chemokine / Interleukin / CXCR / MEMBRANE PROTEIN / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


regulation of single stranded viral RNA replication via double stranded DNA intermediate / regulation of entry of bacterium into host cell / interleukin-8 receptor binding / regulation of chemokine production / interleukin-8 receptor activity / interleukin-8 binding / negative regulation of cell adhesion molecule production / chemokine receptor activity / ATF4 activates genes in response to endoplasmic reticulum stress / CXCR chemokine receptor binding ...regulation of single stranded viral RNA replication via double stranded DNA intermediate / regulation of entry of bacterium into host cell / interleukin-8 receptor binding / regulation of chemokine production / interleukin-8 receptor activity / interleukin-8 binding / negative regulation of cell adhesion molecule production / chemokine receptor activity / ATF4 activates genes in response to endoplasmic reticulum stress / CXCR chemokine receptor binding / embryonic digestive tract development / neutrophil activation / respiratory burst / induction of positive chemotaxis / regulation of chemotaxis / C-C chemokine binding / C-C chemokine receptor activity / positive regulation of neutrophil chemotaxis / chemokine activity / Chemokine receptors bind chemokines / negative regulation of G protein-coupled receptor signaling pathway / dendritic cell chemotaxis / Interleukin-10 signaling / cellular response to interleukin-1 / regulation of cell adhesion / neutrophil chemotaxis / regulation of eating behavior / cellular response to fibroblast growth factor stimulus / adenylate cyclase inhibitor activity / T cell migration / positive regulation of protein localization to cell cortex / 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 / response to endoplasmic reticulum stress / secretory granule membrane / cellular response to forskolin / Peptide ligand-binding receptors / calcium-mediated signaling / regulation of mitotic spindle organization / mast cell degranulation / chemokine-mediated signaling pathway / response to molecule of bacterial origin / neuropeptide signaling pathway / Regulation of insulin secretion / cellular response to tumor necrosis factor / receptor internalization / response to prostaglandin E / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / response to peptide hormone / chemotaxis / G protein-coupled receptor activity / positive regulation of angiogenesis / 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 / 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 / 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) / GDP binding / G beta:gamma signalling through BTK / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / 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 / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / heparin binding / antimicrobial humoral immune response mediated by antimicrobial peptide / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / cellular response to prostaglandin E stimulus / GPER1 signaling / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to lipopolysaccharide / G alpha (12/13) signalling events / G-protein beta-subunit binding / extracellular vesicle / positive regulation of cytosolic calcium ion concentration / Thrombin signalling through proteinase activated receptors (PARs)
Similarity search - Function
CXC chemokine receptor 1 / CXC chemokine receptor 1/2 / CXC chemokine / CXC chemokine, conserved site / Small cytokines (intercrine/chemokine) C-x-C subfamily signature. / CXC 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 ...CXC chemokine receptor 1 / CXC chemokine receptor 1/2 / CXC chemokine / CXC chemokine, conserved site / Small cytokines (intercrine/chemokine) C-x-C subfamily signature. / CXC 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 / : / 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 / 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
Interleukin-8 / C-X-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
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.41 Å
AuthorsIshimoto, N. / Park, J.H. / Park, S.Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2023
Title: Structural basis of CXC chemokine receptor 1 ligand binding and activation.
Authors: Naito Ishimoto / Jae-Hyun Park / Kouki Kawakami / Michiko Tajiri / Kenji Mizutani / Satoko Akashi / Jeremy R H Tame / Asuka Inoue / Sam-Yong Park /
Abstract: Neutrophil granulocytes play key roles in innate immunity and shaping adaptive immune responses. They are attracted by chemokines to sites of infection and tissue damage, where they kill and ...Neutrophil granulocytes play key roles in innate immunity and shaping adaptive immune responses. They are attracted by chemokines to sites of infection and tissue damage, where they kill and phagocytose bacteria. The chemokine CXCL8 (also known as interleukin-8, abbreviated IL-8) and its G-protein-coupled receptors CXCR1 and CXCR2 are crucial elements in this process, and also the development of many cancers. These GPCRs have therefore been the target of many drug development campaigns and structural studies. Here, we solve the structure of CXCR1 complexed with CXCL8 and cognate G-proteins using cryo-EM, showing the detailed interactions between the receptor, the chemokine and Gαi protein. Unlike the closely related CXCR2, CXCR1 strongly prefers to bind CXCL8 in its monomeric form. The model shows that steric clashes would form between dimeric CXCL8 and extracellular loop 2 (ECL2) of CXCR1. Consistently, transplanting ECL2 of CXCR2 onto CXCR1 abolishes the selectivity for the monomeric chemokine. Our model and functional analysis of various CXCR1 mutants will assist efforts in structure-based drug design targeting specific CXC chemokine receptor subtypes.
History
DepositionFeb 10, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 19, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: C-X-C chemokine receptor type 1
B: Guanine nucleotide-binding protein G(i) subunit alpha-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
E: scFv16
F: Interleukin-8


Theoretical massNumber of molelcules
Total (without water)163,3976
Polymers163,3976
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules AF

#1: Protein C-X-C chemokine receptor type 1 / CXC-R1 / CXCR-1 / CDw128a / High affinity interleukin-8 receptor A / IL-8R A / IL-8 receptor type 1


Mass: 40935.199 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CXCR1, CMKAR1, IL8RA / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P25024
#6: Protein Interleukin-8 / IL-8 / C-X-C motif chemokine 8 / Chemokine (C-X-C motif) ligand 8 / Emoctakin / Granulocyte ...IL-8 / C-X-C motif chemokine 8 / Chemokine (C-X-C motif) ligand 8 / Emoctakin / Granulocyte chemotactic protein 1 / GCP-1 / Monocyte-derived neutrophil chemotactic factor / MDNCF / Monocyte-derived neutrophil-activating peptide / MONAP / Neutrophil-activating protein 1 / NAP-1 / Protein 3-10C / T-cell chemotactic factor


Mass: 8401.807 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CXCL8, IL8 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P10145

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

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


Mass: 40415.031 Da / Num. of mol.: 1
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
#3: 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
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 8506.765 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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Antibody , 1 types, 1 molecules E

#5: Antibody scFv16


Mass: 27409.588 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)

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Details

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: Cryo-EM structure of human chemokine receptor 1 / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightValue: 0.15 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
Details: 50 mM HEPES pH8.0, 100 mM NaCl, 1 mM MgCl2, 0.5 mM TCEP, 0.001% LMNG, 0.0001% CHS, 1 uM IL8
Buffer component
IDConc.NameFormulaBuffer-ID
150 mM2-[4-(2-Hydroxyethyl)-1-piperazinyl]ethanesulfonic acidHEPES1
2100 mMSodium chlorideNaCl1
31 mMMagnesium chlorideMgCl21
40.5 mMTris(2-carboxyethyl)phosphineTCEP1
50.001 %(w/v)Lauryl Maltose Neopentyl GlycolLMNG1
60.0001 %(w/v)Cholesteryl homosuccinateCHS1
71 uMInterleukin-8IL81
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 K

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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 magnification: 105000 X / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 4.7 sec. / Electron dose: 51.16 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4175

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameVersionCategory
1cryoSPARC3.3.1particle selection
2EPUimage acquisition
4cryoSPARC3.3.1CTF correction
7UCSF ChimeraX1.5model fitting
8Coot0.9.8.3model fitting
10cryoSPARC3.3.1initial Euler assignment
11cryoSPARC3.3.1final Euler assignment
13cryoSPARC3.3.13D reconstruction
14PHENIX1.2model refinement
CTF correctionType: NONE
Particle selectionNum. of particles selected: 2046429
3D reconstructionResolution: 3.41 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 120631 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0039752
ELECTRON MICROSCOPYf_angle_d0.51913209
ELECTRON MICROSCOPYf_dihedral_angle_d4.241327
ELECTRON MICROSCOPYf_chiral_restr0.0411511
ELECTRON MICROSCOPYf_plane_restr0.0041665

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