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- EMDB-25176: Cryo-EM structure of human ACKR3 in complex with CXCL12, a small ... -

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Basic information

Entry
Database: EMDB / ID: EMD-25176
TitleCryo-EM structure of human ACKR3 in complex with CXCL12, a small molecule partial agonist CCX662, an extracellular Fab, and an intracellular Fab
Map data
Sample
  • Complex: Complex structure of CID25-ACKR3-CXCL12-CCX662-CID24
    • Protein or peptide: Atypical chemokine receptor 3
    • Protein or peptide: Stromal cell-derived factor 1
    • Protein or peptide: CID25 Fab light chain
    • Protein or peptide: CID25 Fab heavy chain
    • Protein or peptide: CID24 Fab light chain
    • Protein or peptide: CID24 Fab heavy chain
  • Ligand: CHOLESTEROL
  • Ligand: Lauryl Maltose Neopentyl Glycol
  • Ligand: (1R)-4-[7-(3-carboxypropoxy)-6-methylquinolin-8-yl]-1-{[2-(4-hydroxypiperidin-1-yl)-1,3-thiazol-4-yl]methyl}-1,4-diazepan-1-ium
KeywordsAtypical 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 / positive regulation of endothelial cell proliferation / clathrin-coated pit / 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)
Similarity search - Domain/homology
Atypical chemokine receptor 3 / Stromal cell-derived factor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsYen YC / Schafer CT / Gustavsson M / Handel TM / Tesmer JJG
Funding support United States, 7 items
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, 2021-
Header (metadata) releaseJul 27, 2022-
Map releaseJul 27, 2022-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25176.png

Downloads & links

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Map

FileDownload / File: emd_25176.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 300 pix.
= 324. Å		1.08 Å/pix.
x 300 pix.
= 324. Å		1.08 Å/pix.
x 300 pix.
= 324. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.86
Minimum - Maximum-4.321492 - 6.123186
Average (Standard dev.)0.0011026831 (±0.08338265)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 324.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Complex structure of CID25-ACKR3-CXCL12-CCX662-CID24

EntireName: Complex structure of CID25-ACKR3-CXCL12-CCX662-CID24
Components
  • Complex: Complex structure of CID25-ACKR3-CXCL12-CCX662-CID24
    • Protein or peptide: Atypical chemokine receptor 3
    • Protein or peptide: Stromal cell-derived factor 1
    • Protein or peptide: CID25 Fab light chain
    • Protein or peptide: CID25 Fab heavy chain
    • Protein or peptide: CID24 Fab light chain
    • Protein or peptide: CID24 Fab heavy chain
  • Ligand: CHOLESTEROL
  • Ligand: Lauryl Maltose Neopentyl Glycol
  • Ligand: (1R)-4-[7-(3-carboxypropoxy)-6-methylquinolin-8-yl]-1-{[2-(4-hydroxypiperidin-1-yl)-1,3-thiazol-4-yl]methyl}-1,4-diazepan-1-ium

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Supramolecule #1: Complex structure of CID25-ACKR3-CXCL12-CCX662-CID24

SupramoleculeName: Complex structure of CID25-ACKR3-CXCL12-CCX662-CID24 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6

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Macromolecule #1: Atypical chemokine receptor 3

MacromoleculeName: Atypical chemokine receptor 3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.196406 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GAPDLHLFDY SEPGNFSDIS WPCNSSDCIV VDTVMCPNMP NKSVLLYTLS FIYIFIFVIG MIANSVVVWV NIQAKTTGYD THCYILNLA IADLWVVLTI PVWVVSLVQH NQWPMGELTC KVTHLIFSIN LFGSIFFLTC MSVDRYLSIT YFTNTPSSRK K MVRRVVCI ...String:
GAPDLHLFDY SEPGNFSDIS WPCNSSDCIV VDTVMCPNMP NKSVLLYTLS FIYIFIFVIG MIANSVVVWV NIQAKTTGYD THCYILNLA IADLWVVLTI PVWVVSLVQH NQWPMGELTC KVTHLIFSIN LFGSIFFLTC MSVDRYLSIT YFTNTPSSRK K MVRRVVCI LVWLLAFCVS LPDTYYLKTV TSASNNETYC RSFYPEHSIK EWLIGMELVS VVLGFAVPFS IIAVFYFLLA RA ISASSDQ EKHSSRKIIF SYVVVFLVCW LPYHVAVLLD IFSILHYIPF TCRLEHALFT ALHVTQCLSL VHCCVNPVLY SFI NRNYRY ELMKAFIFKY SAKTGLTKLI DASRVSETEY SALEQSTKGR PLEVLFQGPH HHHHHHHHHD YKDDDDK

UniProtKB: Atypical chemokine receptor 3

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Macromolecule #2: Stromal cell-derived factor 1

MacromoleculeName: Stromal cell-derived factor 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.97846 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
KPVSLSYRCP CRFFESHVAR ANVKHLKILN TPNCALQIVA RLKNNNRQVC IDPKLKWIQE YLEKALNK

UniProtKB: Stromal cell-derived factor 1

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Macromolecule #3: CID25 Fab light chain

MacromoleculeName: CID25 Fab light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.531129 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString: SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQYYYPLFTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQYYYPLFTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #4: CID25 Fab heavy chain

MacromoleculeName: CID25 Fab heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.461383 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString: EISEVQLVES GGGLVQPGGS LRLSCAASGF NFSYSSIHWV RQAPGKGLEW VAYIYSSYGY TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARVYPWWYYK YYHGALDYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD Y FPEPVTVS ...String:
EISEVQLVES GGGLVQPGGS LRLSCAASGF NFSYSSIHWV RQAPGKGLEW VAYIYSSYGY TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARVYPWWYYK YYHGALDYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD Y FPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHT

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Macromolecule #5: CID24 Fab light chain

MacromoleculeName: CID24 Fab light chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.471031 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString: SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQSYYYPITF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQSYYYPITF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #6: CID24 Fab heavy chain

MacromoleculeName: CID24 Fab heavy chain / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.380223 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString: EISEVQLVES GGGLVQPGGS LRLSCAASGF NISSSSIHWV RQAPGKGLEW VASISPSYGY TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARVSYWDWTW GWSKYEGMDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV K DYFPEPVT ...String:
EISEVQLVES GGGLVQPGGS LRLSCAASGF NISSSSIHWV RQAPGKGLEW VASISPSYGY TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARVSYWDWTW GWSKYEGMDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV K DYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKKV EPKSCDKTHT

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Macromolecule #7: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 7 / Number of copies: 6 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #8: Lauryl Maltose Neopentyl Glycol

MacromoleculeName: Lauryl Maltose Neopentyl Glycol / type: ligand / ID: 8 / Number of copies: 1 / Formula: LMN
Molecular weightTheoretical: 1.005188 KDa
Chemical component information

ChemComp-AV0:
Lauryl Maltose Neopentyl Glycol

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Macromolecule #9: (1R)-4-[7-(3-carboxypropoxy)-6-methylquinolin-8-yl]-1-{[2-(4-hydr...

MacromoleculeName: (1R)-4-[7-(3-carboxypropoxy)-6-methylquinolin-8-yl]-1-{[2-(4-hydroxypiperidin-1-yl)-1,3-thiazol-4-yl]methyl}-1,4-diazepan-1-ium
type: ligand / ID: 9 / Number of copies: 1 / Formula: GJ9
Molecular weightTheoretical: 540.697 Da
Chemical component information

ChemComp-GJ9:
(1R)-4-[7-(3-carboxypropoxy)-6-methylquinolin-8-yl]-1-{[2-(4-hydroxypiperidin-1-yl)-1,3-thiazol-4-yl]methyl}-1,4-diazepan-1-ium

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.2 mg/mL
BufferpH: 8
Component:
ConcentrationNameFormula
20.0 mMHEPES
100.0 mMsodium chlorideNaCl
0.01 %LMNG
0.001 %CHS
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 53.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 605556
Initial angle assignmentType: COMMON LINE / Software - Name: cryoSPARC
Final angle assignmentType: COMMON LINE / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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