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- PDB-7sk5: Cryo-EM structure of ACKR3 in complex with CXCL12 and an intracel... -

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Basic information

Entry
Database: PDB / ID: 7sk5
TitleCryo-EM structure of ACKR3 in complex with CXCL12 and an intracellular Fab
Components
  • Anti-Fab nanobody
  • Atypical chemokine receptor 3
  • CID24 Fab heavy chain
  • CID24 Fab light chain
  • Stromal cell-derived factor 1
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / Atypical Chemokine Receptor / MEMBRANE PROTEIN / SIGNALING PROTEIN / SIGNALING PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


oculomotor nerve development / positive regulation of mesenchymal stem cell migration / telencephalon cell migration / chemokine (C-X-C motif) ligand 12 signaling pathway / negative regulation of leukocyte tethering or rolling / response to ultrasound / regulation of actin polymerization or depolymerization / chemokine receptor binding / C-X-C chemokine binding / CXCL12-activated CXCR4 signaling pathway ...oculomotor nerve development / positive regulation of mesenchymal stem cell migration / telencephalon cell migration / chemokine (C-X-C motif) ligand 12 signaling pathway / negative regulation of leukocyte tethering or rolling / response to ultrasound / regulation of actin polymerization or depolymerization / chemokine receptor binding / C-X-C chemokine binding / CXCL12-activated CXCR4 signaling pathway / 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 / induction of positive chemotaxis / integrin activation / negative regulation of dendritic cell apoptotic process / C-C chemokine receptor activity / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / cellular response to chemokine / chemokine-mediated signaling pathway / C-C chemokine binding / positive regulation of monocyte chemotaxis / chemokine activity / blood circulation / Chemokine receptors bind chemokines / scavenger receptor activity / positive regulation of calcium ion import / detection of temperature stimulus involved in sensory perception of pain / animal organ regeneration / detection of mechanical stimulus involved in sensory perception of pain / positive regulation of T cell migration / vasculogenesis / Nuclear signaling by ERBB4 / coreceptor activity / clathrin-coated pit / positive regulation of endothelial cell proliferation / positive regulation of neuron differentiation / positive regulation of cell adhesion / axon guidance / adult locomotory behavior / cell chemotaxis / growth factor activity / calcium-mediated signaling / defense response / response to peptide hormone / recycling endosome / receptor internalization / response to virus / integrin binding / neuron migration / intracellular calcium ion homeostasis / chemotaxis / : / positive regulation of cytosolic calcium ion concentration / angiogenesis / G alpha (i) signalling events / Estrogen-dependent gene expression / early endosome / response to hypoxia / positive regulation of ERK1 and ERK2 cascade / cell adhesion / endosome / immune response / positive regulation of cell migration / G protein-coupled receptor signaling pathway / signaling receptor binding / negative regulation of cell population proliferation / external side of plasma membrane / intracellular membrane-bounded organelle / cell surface / signal transduction / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Atypical chemokine receptor 3 / : / 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 / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like ...Atypical chemokine receptor 3 / : / 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 / 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) / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
CHOLESTEROL / Atypical chemokine receptor 3 / Stromal cell-derived factor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsYen, Y.C. / Schafer, C.T. / Gustavsson, M. / Handel, T.M. / Tesmer, J.J.G.
Funding support United States, 7items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA254402 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI161880 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA221289 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL071818 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA023168 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM137505 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM117372 United States
CitationJournal: Sci Adv / Year: 2022
Title: Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias.
Authors: Yu-Chen Yen / Christopher T Schafer / Martin Gustavsson / Stefanie A Eberle / Pawel K Dominik / Dawid Deneka / Penglie Zhang / Thomas J Schall / Anthony A Kossiakoff / John J G Tesmer / Tracy M Handel /
Abstract: Both CXC chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are activated by the chemokine CXCL12 yet evoke distinct cellular responses. CXCR4 is a canonical G protein-coupled ...Both CXC chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are activated by the chemokine CXCL12 yet evoke distinct cellular responses. CXCR4 is a canonical G protein-coupled receptor (GPCR), whereas ACKR3 is intrinsically biased for arrestin. The molecular basis for this difference is not understood. Here, we describe cryo-EM structures of ACKR3 in complex with CXCL12, a more potent CXCL12 variant, and a small-molecule agonist. The bound chemokines adopt an unexpected pose relative to those established for CXCR4 and observed in other receptor-chemokine complexes. Along with functional studies, these structures provide insight into the ligand-binding promiscuity of ACKR3, why it fails to couple to G proteins, and its bias toward β-arrestin. The results lay the groundwork for understanding the physiological interplay of ACKR3 with other GPCRs.
History
DepositionOct 19, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 27, 2022Provider: repository / Type: Initial release
Revision 1.0Jul 27, 2022Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 27, 2022Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 27, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 27, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Jul 27, 2022Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 27, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 27, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Oct 23, 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 / _pdbx_entry_details.has_protein_modification
Revision 1.2Jun 4, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jun 4, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Atypical chemokine receptor 3
F: CID24 Fab heavy chain
B: Stromal cell-derived factor 1
E: CID24 Fab light chain
K: Anti-Fab nanobody
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,12312
Polymers115,4175
Non-polymers2,7077
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Atypical chemokine receptor 3 / C-X-C chemokine receptor type 7 / CXC-R7 / CXCR-7 / Chemokine orphan receptor 1 / G-protein coupled ...C-X-C chemokine receptor type 7 / CXC-R7 / CXCR-7 / Chemokine orphan receptor 1 / G-protein coupled receptor 159 / G-protein coupled receptor RDC1 homolog / RDC-1


Mass: 45196.406 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACKR3, CMKOR1, CXCR7, GPR159, RDC1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P25106
#3: Protein Stromal cell-derived factor 1 / hSDF-1 / C-X-C motif chemokine 12 / Intercrine reduced in hepatomas / hIRH / Pre-B cell growth- ...hSDF-1 / C-X-C motif chemokine 12 / Intercrine reduced in hepatomas / hIRH / Pre-B cell growth-stimulating factor / PBSF


Mass: 7978.460 Da / Num. of mol.: 1 / Fragment: UNP residues 22-89
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CXCL12, SDF1, SDF1A, SDF1B
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P48061

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Antibody , 3 types, 3 molecules FEK

#2: Antibody CID24 Fab heavy chain


Mass: 25380.223 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
#4: Antibody CID24 Fab light chain


Mass: 23471.031 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
#5: Antibody Anti-Fab nanobody


Mass: 13390.644 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama)
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)

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Non-polymers , 1 types, 7 molecules

#6: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 7 / 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: Complex structure of ACKR3-CXCL12-CID24-NB / Type: COMPLEX / Entity ID: #1-#5 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPES1
2100 mMsodium chlorideNaCl1
30.01 %LMNG1
40.001 %CHS1
SpecimenConc.: 0.2 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: 277 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 defocus max: 3000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 53.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20_4459: / Classification: refinement
EM software
IDNameCategory
2Leginonimage acquisition
4cryoSPARCCTF correction
9PHENIXmodel refinement
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 397340 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0027431
ELECTRON MICROSCOPYf_angle_d0.42810157
ELECTRON MICROSCOPYf_dihedral_angle_d13.9162593
ELECTRON MICROSCOPYf_chiral_restr0.0391175
ELECTRON MICROSCOPYf_plane_restr0.0031226

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