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- PDB-8k3z: Cryo-EM structure of CXCR4 in complex with CXCL12 -

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Basic information

Entry
Database: PDB / ID: 8k3z
TitleCryo-EM structure of CXCR4 in complex with CXCL12
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • C-X-C chemokine receptor type 4
  • Stromal cell-derived factor 1
  • scFv16
KeywordsIMMUNE SYSTEM / Chemokine receptor / CXCR4
Function / homology
Function and homology information


C-X-C motif chemokine 12 receptor activity / telencephalon cell migration / chemokine (C-X-C motif) ligand 12 signaling pathway / negative regulation of leukocyte tethering or rolling / response to ultrasound / positive regulation of macrophage migration inhibitory factor signaling pathway / regulation of actin polymerization or depolymerization / chemokine receptor binding / Specification of primordial germ cells / CXCL12-activated CXCR4 signaling pathway ...C-X-C motif chemokine 12 receptor activity / telencephalon cell migration / chemokine (C-X-C motif) ligand 12 signaling pathway / negative regulation of leukocyte tethering or rolling / response to ultrasound / positive regulation of macrophage migration inhibitory factor signaling pathway / regulation of actin polymerization or depolymerization / chemokine receptor binding / Specification of primordial germ cells / CXCL12-activated CXCR4 signaling pathway / myosin light chain binding / myelin maintenance / CXCR chemokine receptor binding / C-X-C chemokine receptor activity / positive regulation of axon extension involved in axon guidance / positive regulation of vasculature development / positive regulation of dopamine secretion / Signaling by ROBO receptors / regulation of chemotaxis / induction of positive chemotaxis / Formation of definitive endoderm / C-C chemokine receptor activity / integrin activation / negative regulation of dendritic cell apoptotic process / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / cellular response to chemokine / chemokine-mediated signaling pathway / C-C chemokine binding / Developmental Lineage of Pancreatic Acinar Cells / positive regulation of monocyte chemotaxis / chemokine activity / Chemokine receptors bind chemokines / blood circulation / anchoring junction / dendritic cell chemotaxis / positive regulation of calcium ion import / cell leading edge / cellular response to cytokine stimulus / detection of temperature stimulus involved in sensory perception of pain / positive regulation of oligodendrocyte differentiation / animal organ regeneration / Binding and entry of HIV virion / positive regulation of T cell migration / detection of mechanical stimulus involved in sensory perception of pain / adenylate cyclase inhibitor activity / regulation of cell adhesion / Nuclear signaling by ERBB4 / positive regulation of protein localization to cell cortex / T cell migration / Adenylate cyclase inhibitory pathway / coreceptor activity / D2 dopamine receptor binding / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / neurogenesis / positive regulation of endothelial cell proliferation / positive regulation of neuron differentiation / cellular response to forskolin / positive regulation of cell adhesion / regulation of mitotic spindle organization / axon guidance / adult locomotory behavior / ubiquitin binding / cell chemotaxis / Regulation of insulin secretion / growth factor activity / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor binding / calcium-mediated signaling / G protein-coupled receptor activity / defense response / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / brain development / response to peptide hormone / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / response to virus / centriolar satellite / 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 / intracellular calcium ion homeostasis / 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 / neuron migration / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / chemotaxis / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste
Similarity search - Function
CXC chemokine receptor 4 N-terminal domain / CXCR4 Chemokine receptor N terminal / CXC chemokine receptor 4/atypical chemokine receptor 2 / CXC Chemokine domain / 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 ...CXC chemokine receptor 4 N-terminal domain / CXCR4 Chemokine receptor N terminal / CXC chemokine receptor 4/atypical chemokine receptor 2 / CXC Chemokine domain / 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 / 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 / G protein beta WD-40 repeat protein / 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. / 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
Stromal cell-derived factor 1 / 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)
Vicugna pacos (alpaca)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.81 Å
AuthorsLiu, Y.Z. / Liu, A.J. / Liao, Q.W. / Ye, R.D.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cell Rep / Year: 2024
Title: Cryo-EM structure of monomeric CXCL12-bound CXCR4 in the active state.
Authors: Yezhou Liu / Aijun Liu / Xinyu Li / Qiwen Liao / Weijia Zhang / Lizhe Zhu / Richard D Ye /
Abstract: CXCR4 binding of its endogenous agonist CXCL12 leads to diverse functions, including bone marrow retention of hematopoietic progenitors and cancer metastasis. However, the structure of the CXCL12- ...CXCR4 binding of its endogenous agonist CXCL12 leads to diverse functions, including bone marrow retention of hematopoietic progenitors and cancer metastasis. However, the structure of the CXCL12-bound CXCR4 remains unresolved despite available structures of CXCR4 in complex with antagonists. Here, we present the cryoelectron microscopy (cryo-EM) structure of the CXCL12-CXCR4-Gi complex at an overall resolution of 2.65 Å. CXCL12 forms a 1:1 stoichiometry complex with CXCR4, following the two-site model. The first 8 amino acids of mature CXCL12 are crucial for CXCR4 activation by forming polar interactions with minor sub-pocket residues in the transmembrane binding pocket. The 3.2-Å distance between V3 of CXCL12 and the "toggle switch" W marks the deepest insertion among all chemokine-receptor pairs, leading to conformational changes of CXCR4 for G protein activation. These results, combined with functional assays and computational analysis, provide the structural basis for CXCR4 activation by CXCL12.
History
DepositionJul 17, 2023Deposition site: PDBJ / Processing site: PDBJ
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Revision 1.1Nov 13, 2024Group: Data collection / Structure summary
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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 4
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(i) subunit alpha-1
D: Stromal cell-derived factor 1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
S: scFv16


Theoretical massNumber of molelcules
Total (without water)151,2016
Polymers151,2016
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

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Protein , 2 types, 2 molecules AD

#1: Protein C-X-C chemokine receptor type 4 / CXC-R4 / CXCR-4 / FB22 / Fusin / HM89 / LCR1 / Leukocyte-derived seven transmembrane domain ...CXC-R4 / CXCR-4 / FB22 / Fusin / HM89 / LCR1 / Leukocyte-derived seven transmembrane domain receptor / LESTR / Lipopolysaccharide-associated protein 3 / LAP-3 / LPS-associated protein 3 / NPYRL / Stromal cell-derived factor 1 receptor / SDF-1 receptor


Mass: 33826.059 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
#4: Protein Stromal cell-derived factor 1 / SDF-1 / hSDF-1 / C-X-C motif chemokine 12 / Intercrine reduced in hepatomas / IRH / hIRH / Pre-B ...SDF-1 / hSDF-1 / C-X-C motif chemokine 12 / Intercrine reduced in hepatomas / IRH / hIRH / Pre-B cell growth-stimulating factor / PBSF


Mass: 7292.648 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CXCL12, SDF1, SDF1A, SDF1B / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P48061

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

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


Mass: 37198.656 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) 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
#5: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 6131.084 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 S

#6: Antibody scFv16


Mass: 26337.307 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Vicugna pacos (alpaca) / 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: CXCR4-CXCL12-Gi-scFv16 complex / Type: COMPLEX / Entity ID: #6, #5, #2-#3, #1, #4 / Source: RECOMBINANT
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
Specimen supportGrid material: GOLD
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: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.81 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 373108 / Symmetry type: POINT

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