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- PDB-8xxr: Structure of CXCR2 bound to CXCL6 (CXCR2-CXCL6-Go Full map) -

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Basic information

Entry
Database: PDB / ID: 8xxr
TitleStructure of CXCR2 bound to CXCL6 (CXCR2-CXCL6-Go Full map)
Components
  • Antibody fragment ScFv16
  • C-X-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(o) subunit alpha
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / GPCR / Arrestin / SIGNALING PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


interleukin-8-mediated signaling pathway / metanephric tubule morphogenesis / negative regulation of neutrophil apoptotic process / mast cell granule / interleukin-8 receptor activity / interleukin-8 binding / acute inflammatory response to antigenic stimulus / C-X-C chemokine receptor activity / neutrophil activation / mu-type opioid receptor binding ...interleukin-8-mediated signaling pathway / metanephric tubule morphogenesis / negative regulation of neutrophil apoptotic process / mast cell granule / interleukin-8 receptor activity / interleukin-8 binding / acute inflammatory response to antigenic stimulus / C-X-C chemokine receptor activity / neutrophil activation / mu-type opioid receptor binding / C-C chemokine receptor activity / corticotropin-releasing hormone receptor 1 binding / C-C chemokine binding / positive regulation of vascular permeability / vesicle docking involved in exocytosis / positive regulation of neutrophil chemotaxis / Chemokine receptors bind chemokines / dendritic cell chemotaxis / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction / parallel fiber to Purkinje cell synapse / midbrain development / postsynaptic modulation of chemical synaptic transmission / negative regulation of insulin secretion / cellular defense response / positive regulation of cardiac muscle cell apoptotic process / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / adenylate cyclase regulator activity / muscle contraction / neutrophil chemotaxis / secretory granule membrane / GABA-ergic synapse / locomotory behavior / calcium-mediated signaling / G protein-coupled receptor activity / receptor internalization / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / mitotic spindle / 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 / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / positive regulation of angiogenesis / Vasopressin regulates renal water homeostasis via Aquaporins / chemotaxis / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / microtubule cytoskeleton / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / G protein activity / presynaptic membrane / cell body / GTPase binding / Ca2+ pathway / retina development in camera-type eye / positive regulation of cytosolic calcium ion concentration / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (s) signalling events / G alpha (q) signalling events / postsynaptic membrane / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / cell surface receptor signaling pathway
Similarity search - Function
CXC chemokine receptor 2 / CXC chemokine receptor 1/2 / : / G-protein alpha subunit, group I / 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 ...CXC chemokine receptor 2 / CXC chemokine receptor 1/2 / : / G-protein alpha subunit, group I / 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
Guanine nucleotide-binding protein G(o) subunit alpha / C-X-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
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.17 Å
AuthorsSano, F.K. / Saha, S. / Sharma, S. / Ganguly, M. / Shihoya, W. / Nureki, O. / Shukla, A.K. / Banerjee, R.
Funding support India, 1items
OrganizationGrant numberCountry
Science and Engineering Research Board (SERB)IPA/2020/000405 India
CitationJournal: Mol Cell / Year: 2025
Title: Molecular basis of promiscuous chemokine binding and structural mimicry at the C-X-C chemokine receptor, CXCR2.
Authors: Shirsha Saha / Fumiya K Sano / Saloni Sharma / Manisankar Ganguly / Sudha Mishra / Annu Dalal / Hiroaki Akasaka / Takaaki A Kobayashi / Nashrah Zaidi / Divyanshu Tiwari / Nabarun Roy / ...Authors: Shirsha Saha / Fumiya K Sano / Saloni Sharma / Manisankar Ganguly / Sudha Mishra / Annu Dalal / Hiroaki Akasaka / Takaaki A Kobayashi / Nashrah Zaidi / Divyanshu Tiwari / Nabarun Roy / Manish K Yadav / Nilanjana Banerjee / Sayantan Saha / Samanwita Mohapatra / Yuzuru Itoh / Andy Chevigné / Ramanuj Banerjee / Wataru Shihoya / Osamu Nureki / Arun K Shukla /
Abstract: Selectivity of natural agonists for their cognate receptors is a hallmark of G-protein-coupled receptors (GPCRs); however, this selectivity often breaks down at the chemokine receptors. Chemokines ...Selectivity of natural agonists for their cognate receptors is a hallmark of G-protein-coupled receptors (GPCRs); however, this selectivity often breaks down at the chemokine receptors. Chemokines often display promiscuous binding to chemokine receptors, but the underlying molecular determinants remain mostly elusive. Here, we perform a comprehensive transducer-coupling analysis, testing all known C-X-C chemokines on every C-X-C type chemokine receptor to generate a global fingerprint of the selectivity and promiscuity encoded within this system. Taking lead from this, we determine cryoelectron microscopy (cryo-EM) structures of the most promiscuous receptor, C-X-C chemokine receptor 2 (CXCR2), in complex with several chemokines. These structural snapshots elucidate the details of ligand-receptor interactions, including structural motifs, which are validated using mutagenesis and functional experiments. We also observe that most chemokines position themselves on CXCR2 as a dimer while CXCL6 exhibits a monomeric binding pose. Taken together, our findings provide the molecular basis of chemokine promiscuity at CXCR2 with potential implications for developing therapeutic molecules.
History
DepositionJan 18, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 15, 2025Provider: repository / Type: Initial release
Revision 1.1Apr 9, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
R: C-X-C chemokine receptor type 2
A: Guanine nucleotide-binding protein G(o) subunit alpha
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
S: Antibody fragment ScFv16


Theoretical massNumber of molelcules
Total (without water)146,5865
Polymers146,5865
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein C-X-C chemokine receptor type 2 / CXC-R2 / CXCR-2


Mass: 46699.609 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CXCR2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P25025
#2: Protein Guanine nucleotide-binding protein G(o) subunit alpha


Mass: 27024.762 Da / Num. of mol.: 1 / Mutation: G42D,E43N,A227D,G230D,I332A,V335I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAO1 / Production host: Escherichia coli (E. coli) / References: UniProt: P09471
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38534.062 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: 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
#5: Antibody Antibody fragment ScFv16


Mass: 26466.486 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Escherichia coli (E. coli)
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: C-X-C chemokine receptor type 2 in complex with C-X-C motif chemokine 6 and Go
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
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: 1600 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 49.8 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 (6k x 4k)
Image scansMovie frames/image: 40

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Processing

EM software
IDNameVersionCategory
4cryoSPARC4.4CTF correction
7Cootmodel fitting
9PHENIXmodel refinement
12cryoSPARC4.4classification
13cryoSPARC4.43D reconstruction
14RELION43D reconstruction
CTF correctionType: NONE
Particle selectionNum. of particles selected: 1609421
3D reconstructionResolution: 3.17 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 61539 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingSource name: SwissModel / Type: in silico model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0068854
ELECTRON MICROSCOPYf_angle_d0.59212018
ELECTRON MICROSCOPYf_dihedral_angle_d3.8161220
ELECTRON MICROSCOPYf_chiral_restr0.0411393
ELECTRON MICROSCOPYf_plane_restr0.0041518

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