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- EMDB-25175: Cryo-EM structure of human ACKR3 in complex with CXCL12, a small ... -

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Basic information

Entry
Database: EMDB / ID: EMD-25175
TitleCryo-EM structure of human ACKR3 in complex with CXCL12, a small molecule partial agonist CCX662, and an extracellular Fab
Map data
Sample
  • Complex: Complex structure of NB-CID25-ACKR3-CXCL12-CCX662
    • 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: Anti-Fab nanobody
  • 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
  • Ligand: CHOLESTEROL
Function / homology
Function and homology information


oculomotor nerve development / chemokine (C-X-C motif) ligand 12 signaling pathway / negative regulation of leukocyte tethering or rolling / positive regulation of mesenchymal stem cell migration / response to ultrasound / C-X-C chemokine binding / telencephalon cell migration / regulation of actin polymerization or depolymerization / C-X-C chemokine receptor activity / CXCL12-activated CXCR4 signaling pathway ...oculomotor nerve development / chemokine (C-X-C motif) ligand 12 signaling pathway / negative regulation of leukocyte tethering or rolling / positive regulation of mesenchymal stem cell migration / response to ultrasound / C-X-C chemokine binding / telencephalon cell migration / regulation of actin polymerization or depolymerization / C-X-C chemokine receptor activity / CXCL12-activated CXCR4 signaling pathway / chemokine receptor binding / positive regulation of vasculature development / CXCR chemokine receptor binding / positive regulation of axon extension involved in axon guidance / positive regulation of dopamine secretion / C-C chemokine receptor activity / Signaling by ROBO receptors / scavenger receptor activity / C-C chemokine binding / induction of positive chemotaxis / integrin activation / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / negative regulation of dendritic cell apoptotic process / cellular response to chemokine / chemokine-mediated signaling pathway / blood circulation / positive regulation of monocyte chemotaxis / Chemokine receptors bind chemokines / chemokine activity / positive regulation of calcium ion import / detection of temperature stimulus involved in sensory perception of pain / positive regulation of cell adhesion / positive regulation of T cell migration / vasculogenesis / animal organ regeneration / coreceptor activity / detection of mechanical stimulus involved in sensory perception of pain / clathrin-coated pit / Nuclear signaling by ERBB4 / positive regulation of endothelial cell proliferation / positive regulation of neuron differentiation / cell chemotaxis / adult locomotory behavior / calcium-mediated signaling / axon guidance / neuron migration / growth factor activity / response to virus / receptor internalization / recycling endosome / response to peptide hormone / defense response / intracellular calcium ion homeostasis / chemotaxis / integrin binding / G alpha (i) signalling events / positive regulation of cytosolic calcium ion concentration / angiogenesis / collagen-containing extracellular matrix / Estrogen-dependent gene expression / early endosome / positive regulation of ERK1 and ERK2 cascade / response to hypoxia / cell adhesion / endosome / immune response / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation / external side of plasma membrane / signaling receptor binding / 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) / Lama glama (llama)
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-
UpdateJul 27, 2022-
Current statusJul 27, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25175.png

Downloads & links

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Map

FileDownload / File: emd_25175.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.7
Minimum - Maximum-3.3047187 - 4.780656
Average (Standard dev.)-6.762903e-05 (±0.062439233)
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 NB-CID25-ACKR3-CXCL12-CCX662

EntireName: Complex structure of NB-CID25-ACKR3-CXCL12-CCX662
Components
  • Complex: Complex structure of NB-CID25-ACKR3-CXCL12-CCX662
    • 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: Anti-Fab nanobody
  • 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
  • Ligand: CHOLESTEROL

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

SupramoleculeName: Complex structure of NB-CID25-ACKR3-CXCL12-CCX662 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5

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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

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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

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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: Anti-Fab nanobody

MacromoleculeName: Anti-Fab nanobody / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 13.390644 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GSQVQLQESG GGLVQPGGSL RLSCAASGRT ISRYAMSWFR QAPGKEREFV AVARRSGDGA FYADSVQGRF TVSRDDAKNT VYLQMNSLK PEDTAVYYCA IDSDTFYSGS YDYWGQGTQV TVSS

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Macromolecule #6: (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: 6 / 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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Macromolecule #7: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 7 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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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 chlorideNaClSodium chloride
0.01 %LMNG
0.001 %cholesterol hemisuccinate
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / 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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / 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
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 53.8 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC
Initial angle assignmentType: COMMON LINE / Software - Name: cryoSPARC
Final angle assignmentType: COMMON LINE / Software - Name: cryoSPARC
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: 814168
FSC plot (resolution estimation)

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