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- PDB-7sk9: Cryo-EM structure of human ACKR3 in complex with a small molecule... -

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Basic information

Entry
Database: PDB / ID: 7sk9
TitleCryo-EM structure of human ACKR3 in complex with a small molecule partial agonist CCX662, and an intracellular Fab
Components
  • Atypical chemokine receptor 3
  • CID24 Fab heavy chain
  • CID24 Fab light chain
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 / C-X-C chemokine binding / C-X-C chemokine receptor activity / scavenger receptor activity / C-C chemokine receptor activity / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / C-C chemokine binding / chemokine-mediated signaling pathway / Chemokine receptors bind chemokines ...oculomotor nerve development / positive regulation of mesenchymal stem cell migration / C-X-C chemokine binding / C-X-C chemokine receptor activity / scavenger receptor activity / C-C chemokine receptor activity / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / C-C chemokine binding / chemokine-mediated signaling pathway / Chemokine receptors bind chemokines / vasculogenesis / coreceptor activity / clathrin-coated pit / cell chemotaxis / calcium-mediated signaling / receptor internalization / recycling endosome / G alpha (i) signalling events / positive regulation of cytosolic calcium ion concentration / angiogenesis / positive regulation of ERK1 and ERK2 cascade / early endosome / cell adhesion / endosome / immune response / negative regulation of cell population proliferation / external side of plasma membrane / intracellular membrane-bounded organelle / cell surface / plasma membrane
Similarity search - Function
Atypical chemokine receptor 3 / : / 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
CHOLESTEROL / Chem-GJ9 / Atypical chemokine receptor 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 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

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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
E: CID24 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,3626
Polymers94,0483
Non-polymers1,3143
Water00
1


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

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Components

#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
#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)
#3: 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)
#4: Chemical 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


Mass: 540.697 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H38N5O4S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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-CCX662- CID24 / Type: COMPLEX / Entity ID: #1-#3 / 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 / 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: 1.19.2_4158: / Classification: refinement
EM software
IDNameCategory
2Leginonimage acquisition
4cryoSPARCCTF correction
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 297347 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0035862
ELECTRON MICROSCOPYf_angle_d0.5168006
ELECTRON MICROSCOPYf_dihedral_angle_d5.85804
ELECTRON MICROSCOPYf_chiral_restr0.04922
ELECTRON MICROSCOPYf_plane_restr0.003968

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