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- PDB-8u4n: Structure of Apo CXCR4/Gi complex -

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Basic information

Entry
Database: PDB / ID: 8u4n
TitleStructure of Apo CXCR4/Gi complex
Components
  • C-X-C chemokine receptor type 4
  • 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 / GPCR / chemokine receptor
Function / homology
Function and homology information


C-X-C motif chemokine 12 receptor activity / regulation of viral process / positive regulation of vascular wound healing / positive regulation of macrophage migration inhibitory factor signaling pathway / positive regulation of mesenchymal stem cell migration / neuron recognition / response to ultrasound / telencephalon cell migration / C-X-C chemokine receptor activity / response to tacrolimus ...C-X-C motif chemokine 12 receptor activity / regulation of viral process / positive regulation of vascular wound healing / positive regulation of macrophage migration inhibitory factor signaling pathway / positive regulation of mesenchymal stem cell migration / neuron recognition / response to ultrasound / telencephalon cell migration / C-X-C chemokine receptor activity / response to tacrolimus / Specification of primordial germ cells / CXCL12-activated CXCR4 signaling pathway / myosin light chain binding / myelin maintenance / positive regulation of vasculature development / regulation of programmed cell death / endothelial tube morphogenesis / C-C chemokine receptor activity / endothelial cell differentiation / Signaling by ROBO receptors / regulation of chemotaxis / : / C-C chemokine binding / positive regulation of dendrite extension / positive regulation of chemotaxis / Formation of definitive endoderm / Chemokine receptors bind chemokines / anchoring junction / dendritic cell chemotaxis / positive regulation of oligodendrocyte differentiation / small molecule binding / epithelial cell development / cell leading edge / cellular response to cytokine stimulus / detection of temperature stimulus involved in sensory perception of pain / regulation of calcium ion transport / T cell migration / detection of mechanical stimulus involved in sensory perception of pain / D2 dopamine receptor binding / Binding and entry of HIV virion / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cell adhesion / regulation of cAMP-mediated signaling / coreceptor activity / G protein-coupled serotonin receptor binding / cardiac muscle contraction / cellular response to forskolin / regulation of mitotic spindle organization / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / neurogenesis / cell chemotaxis / ubiquitin binding / response to activity / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / calcium-mediated signaling / neuron migration / brain development / response to virus / 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 / 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 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / response to peptide hormone / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / 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 / GDP binding / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / late endosome
Similarity search - Function
CXC chemokine receptor 4 N-terminal domain / CXCR4 Chemokine receptor N terminal / CXC chemokine receptor 4/atypical chemokine receptor 2 / Chemokine receptor family / : / 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. ...CXC chemokine receptor 4 N-terminal domain / CXCR4 Chemokine receptor N terminal / CXC chemokine receptor 4/atypical chemokine receptor 2 / Chemokine receptor family / : / 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
CHOLESTEROL / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / C-X-C chemokine receptor type 4 / 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: 2.72 Å
AuthorsSaotome, K. / McGoldrick, L.L. / Franklin, M.C.
Funding support United States, 1items
OrganizationGrant numberCountry
Not funded United States
Citation
Journal: Nat Struct Mol Biol / Year: 2024
Title: Structural insights into CXCR4 modulation and oligomerization.
Authors: Kei Saotome / Luke L McGoldrick / Jo-Hao Ho / Trudy F Ramlall / Sweta Shah / Michael J Moore / Jee Hae Kim / Raymond Leidich / William C Olson / Matthew C Franklin /
Abstract: Activation of the chemokine receptor CXCR4 by its chemokine ligand CXCL12 regulates diverse cellular processes. Previously reported crystal structures of CXCR4 revealed the architecture of an ...Activation of the chemokine receptor CXCR4 by its chemokine ligand CXCL12 regulates diverse cellular processes. Previously reported crystal structures of CXCR4 revealed the architecture of an inactive, homodimeric receptor. However, many structural aspects of CXCR4 remain poorly understood. Here, we use cryo-electron microscopy to investigate various modes of human CXCR4 regulation. CXCL12 activates CXCR4 by inserting its N terminus deep into the CXCR4 orthosteric pocket. The binding of US Food and Drug Administration-approved antagonist AMD3100 is stabilized by electrostatic interactions with acidic residues in the seven-transmembrane-helix bundle. A potent antibody blocker, REGN7663, binds across the extracellular face of CXCR4 and inserts its complementarity-determining region H3 loop into the orthosteric pocket. Trimeric and tetrameric structures of CXCR4 reveal modes of G-protein-coupled receptor oligomerization. We show that CXCR4 adopts distinct subunit conformations in trimeric and tetrameric assemblies, highlighting how oligomerization could allosterically regulate chemokine receptor function.
#1: Journal: Biorxiv / Year: 2024
Title: Structural insights into CXCR4 modulation and oligomerization
Authors: Saotome, K. / McGoldrick, L.L. / Ho, J. / Ramlall, T. / Shah, S. / Moore, M.J. / Kim, J.H. / Leidich, R. / Olson, W.C. / Franklin, M.C.
History
DepositionSep 11, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update
Revision 1.2Oct 30, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _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
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
R: C-X-C chemokine receptor type 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)159,4375
Polymers159,0504
Non-polymers3871
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
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: 41591.312 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
#2: 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
#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 C-X-C chemokine receptor type 4


Mass: 71063.609 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CXCR4 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P61073
#5: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O
Has ligand of interestN
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: Apo CXCR4/Gi complex / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightExperimental value: NO
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

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.72 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 183399 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 74.93 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00487113
ELECTRON MICROSCOPYf_angle_d0.65219652
ELECTRON MICROSCOPYf_chiral_restr0.04731118
ELECTRON MICROSCOPYf_plane_restr0.00621205
ELECTRON MICROSCOPYf_dihedral_angle_d5.078958

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