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- EMDB-34917: Structure of CXCR3 complexed with antagonist SCH546738 -

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Basic information

Entry
Database: EMDB / ID: EMD-34917
TitleStructure of CXCR3 complexed with antagonist SCH546738
Map data
Sample
  • Complex: CXCR3-KOR-SCH546738-Nb6
    • Protein or peptide: Nb6
    • Protein or peptide: Soluble cytochrome b562,C-X-C chemokine receptor type 3,Kappa-type opioid receptor
  • Ligand: 3-azanyl-6-chloranyl-5-[(3S)-4-[1-[(4-chlorophenyl)methyl]piperidin-4-yl]-3-ethyl-piperazin-1-yl]pyrazine-2-carboxamide
  • Ligand: CHOLESTEROL
KeywordsG protein coupled receptor / chemokine receptor / CXCR3 / SCH546738 / complex / SIGNALING PROTEIN
Function / homology
Function and homology information


response to acrylamide / adenylate cyclase-inhibiting opioid receptor signaling pathway / dynorphin receptor activity / regulation of saliva secretion / regulation of leukocyte migration / negative regulation of luteinizing hormone secretion / sensory perception of temperature stimulus / positive regulation of eating behavior / chemokine binding / C-X-C chemokine binding ...response to acrylamide / adenylate cyclase-inhibiting opioid receptor signaling pathway / dynorphin receptor activity / regulation of saliva secretion / regulation of leukocyte migration / negative regulation of luteinizing hormone secretion / sensory perception of temperature stimulus / positive regulation of eating behavior / chemokine binding / C-X-C chemokine binding / G protein-coupled opioid receptor activity / chemokine receptor activity / G protein-coupled opioid receptor signaling pathway / C-X-C chemokine receptor activity / positive regulation of dopamine secretion / sensory perception / C-C chemokine receptor activity / positive regulation of potassium ion transmembrane transport / positive regulation of chemotaxis / receptor serine/threonine kinase binding / C-C chemokine binding / maternal behavior / conditioned place preference / negative regulation of execution phase of apoptosis / neuropeptide binding / positive regulation of p38MAPK cascade / Chemokine receptors bind chemokines / eating behavior / negative regulation of endothelial cell proliferation / behavioral response to cocaine / positive regulation of execution phase of apoptosis / neuropeptide signaling pathway / regulation of cell adhesion / estrous cycle / MECP2 regulates neuronal receptors and channels / axon terminus / sensory perception of pain / T-tubule / negative regulation of angiogenesis / positive regulation of release of sequestered calcium ion into cytosol / Peptide ligand-binding receptors / sarcoplasmic reticulum / cell chemotaxis / locomotory behavior / response to insulin / response to nicotine / calcium-mediated signaling / electron transport chain / cellular response to glucose stimulus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / response to estrogen / synaptic vesicle membrane / positive regulation of angiogenesis / chemotaxis / signaling receptor activity / presynaptic membrane / cellular response to lipopolysaccharide / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / angiogenesis / chemical synaptic transmission / defense response to virus / perikaryon / response to ethanol / postsynaptic membrane / periplasmic space / electron transfer activity / cell surface receptor signaling pathway / neuron projection / cell adhesion / immune response / G protein-coupled receptor signaling pathway / inflammatory response / iron ion binding / external side of plasma membrane / apoptotic process / positive regulation of cell population proliferation / heme binding / dendrite / cell surface / positive regulation of transcription by RNA polymerase II / mitochondrion / nucleoplasm / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
CXC chemokine receptor 3 / Kappa opioid receptor / Opioid receptor / Chemokine receptor family / : / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. ...CXC chemokine receptor 3 / Kappa opioid receptor / Opioid receptor / Chemokine receptor family / : / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / 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
Soluble cytochrome b562 / Kappa-type opioid receptor / C-X-C chemokine receptor type 3
Similarity search - Component
Biological speciesHomo sapiens (human) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsJiao HZ / Hu HL
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32100963 China
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Structural insights into the activation and inhibition of CXC chemokine receptor 3.
Authors: Haizhan Jiao / Bin Pang / Aijun Liu / Qiang Chen / Qi Pan / Xiankun Wang / Yunong Xu / Ying-Chih Chiang / Ruobing Ren / Hongli Hu /
Abstract: The chemotaxis of CD4 type 1 helper cells and CD8 cytotoxic lymphocytes, guided by interferon-inducible CXC chemokine 9-11 (CXCL9-11) and CXC chemokine receptor 3 (CXCR3), plays a critical role in ...The chemotaxis of CD4 type 1 helper cells and CD8 cytotoxic lymphocytes, guided by interferon-inducible CXC chemokine 9-11 (CXCL9-11) and CXC chemokine receptor 3 (CXCR3), plays a critical role in type 1 immunity. Here we determined the structures of human CXCR3-DNG complexes activated by chemokine CXCL11, peptidomimetic agonist PS372424 and biaryl-type agonist VUF11222, and the structure of inactive CXCR3 bound to noncompetitive antagonist SCH546738. Structural analysis revealed that PS372424 shares a similar orthosteric binding pocket to the N terminus of CXCL11, while VUF11222 buries deeper and activates the receptor in a distinct manner. We showed an allosteric binding site between TM5 and TM6, accommodating SCH546738 in the inactive CXCR3. SCH546738 may restrain the receptor at an inactive state by preventing the repacking of TM5 and TM6. By revealing the binding patterns and the pharmacological properties of the four modulators, we present the activation mechanisms of CXCR3 and provide insights for future drug development.
History
DepositionDec 8, 2022-
Header (metadata) releaseNov 29, 2023-
Map releaseNov 29, 2023-
UpdateOct 9, 2024-
Current statusOct 9, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_34917.png

Downloads & links

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Map

FileDownload / File: emd_34917.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 280 pix.
= 238. Å		0.85 Å/pix.
x 280 pix.
= 238. Å		0.85 Å/pix.
x 280 pix.
= 238. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.58
Minimum - Maximum-3.9737642 - 5.557085
Average (Standard dev.)-0.0012886183 (±0.08034055)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 238.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_34917_additional_1.map
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Half map: #2

Fileemd_34917_half_map_1.map
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Half map: #1

Fileemd_34917_half_map_2.map
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Sample components

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Entire : CXCR3-KOR-SCH546738-Nb6

EntireName: CXCR3-KOR-SCH546738-Nb6
Components
  • Complex: CXCR3-KOR-SCH546738-Nb6
    • Protein or peptide: Nb6
    • Protein or peptide: Soluble cytochrome b562,C-X-C chemokine receptor type 3,Kappa-type opioid receptor
  • Ligand: 3-azanyl-6-chloranyl-5-[(3S)-4-[1-[(4-chlorophenyl)methyl]piperidin-4-yl]-3-ethyl-piperazin-1-yl]pyrazine-2-carboxamide
  • Ligand: CHOLESTEROL

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Supramolecule #1: CXCR3-KOR-SCH546738-Nb6

SupramoleculeName: CXCR3-KOR-SCH546738-Nb6 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Nb6

MacromoleculeName: Nb6 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 18.665906 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFAMA QVQLQESGGG LVQAGESLRL SCAASGTIFR LYDMGWYRRV SGNQRELVA SITSGGSTKY GDSVKGRFTI SRDNAKNTVY LQMSSLKPED TAVYYCNAEY RTGIWEELLD GWGQGTQVTV S SHHHHHHH H

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Macromolecule #2: Soluble cytochrome b562,C-X-C chemokine receptor type 3,Kappa-typ...

MacromoleculeName: Soluble cytochrome b562,C-X-C chemokine receptor type 3,Kappa-type opioid receptor
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 56.327051 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDKGSADLE DNWETLNDNL KVIEKADNAA QVKDALTKMR AAALDAQKAT PPKLEDKSPD SPEMKDFRH GFDILVGQID DALKLANEGK VKEAQAAAEQ LKTTRNAYIQ KYLLVPRGSM VLEVSDHQVL NDAEVAALLE N FSSSYDYG ...String:
MKTIIALSYI FCLVFADYKD DDDKGSADLE DNWETLNDNL KVIEKADNAA QVKDALTKMR AAALDAQKAT PPKLEDKSPD SPEMKDFRH GFDILVGQID DALKLANEGK VKEAQAAAEQ LKTTRNAYIQ KYLLVPRGSM VLEVSDHQVL NDAEVAALLE N FSSSYDYG ENESDSCCTS PPCPQDFSLN FDRAFLPALY SLLFLLGLLG NGAVAAVLLS RRTALSSTDT FLLHLAVADT LL VLTLPLW AVDAAVQWVF GSGLCKVAGA LFNINFYAGA LLLACISFDR YLNIVHATQL YRRGPPARVT LTCLAVWGLC LLF ALPDFI FLSAHHDERL NATHCQYNFP QVGRTALRVL QLVAGFLLPL LVMAYCYAHI LARLKSVRLL SGSREKDRNL RRIT RLVVV VVVAFALCWT PYHLVVLVDI LMDLGALARN CGRESRVDVA KSVTSGLGYM HCCLNPLLYA FVGVKFRERM WMLLL RLGC PNQRGLQRQP SSSRRDSSWS ETS

UniProtKB: Soluble cytochrome b562, C-X-C chemokine receptor type 3, Kappa-type opioid receptor, C-X-C chemokine receptor type 3

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Macromolecule #3: 3-azanyl-6-chloranyl-5-[(3S)-4-[1-[(4-chlorophenyl)methyl]piperid...

MacromoleculeName: 3-azanyl-6-chloranyl-5-[(3S)-4-[1-[(4-chlorophenyl)methyl]piperidin-4-yl]-3-ethyl-piperazin-1-yl]pyrazine-2-carboxamide
type: ligand / ID: 3 / Number of copies: 1 / Formula: 43I
Molecular weightTheoretical: 492.445 Da
Chemical component information

ChemComp-43I:
3-azanyl-6-chloranyl-5-[(3S)-4-[1-[(4-chlorophenyl)methyl]piperidin-4-yl]-3-ethyl-piperazin-1-yl]pyrazine-2-carboxamide

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
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

Concentration5.0 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 53.43 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: 2.0 µm / Nominal defocus min: 1.5 µm / Nominal magnification: 105000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 509297
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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