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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


regulation of leukocyte migration / response to acrylamide / dynorphin receptor activity / regulation of saliva secretion / chemokine binding / sensory perception of temperature stimulus / C-X-C chemokine binding / positive regulation of eating behavior / adenylate cyclase-inhibiting opioid receptor signaling pathway / Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells) ...regulation of leukocyte migration / response to acrylamide / dynorphin receptor activity / regulation of saliva secretion / chemokine binding / sensory perception of temperature stimulus / C-X-C chemokine binding / positive regulation of eating behavior / adenylate cyclase-inhibiting opioid receptor signaling pathway / Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells) / chemokine receptor activity / negative regulation of luteinizing hormone secretion / C-X-C chemokine receptor activity / G protein-coupled opioid receptor activity / maternal behavior / G protein-coupled opioid receptor signaling pathway / positive regulation of chemotaxis / positive regulation of dopamine secretion / T cell chemotaxis / negative regulation of execution phase of apoptosis / C-C chemokine binding / positive regulation of potassium ion transmembrane transport / receptor serine/threonine kinase binding / positive regulation of p38MAPK cascade / C-C chemokine receptor activity / Chemokine receptors bind chemokines / neuropeptide binding / negative regulation of endothelial cell proliferation / sensory perception / eating behavior / regulation of cell adhesion / positive regulation of execution phase of apoptosis / estrous cycle / conditioned place preference / MECP2 regulates neuronal receptors and channels / behavioral response to cocaine / sensory perception of pain / negative regulation of angiogenesis / T-tubule / locomotory behavior / positive regulation of release of sequestered calcium ion into cytosol / axon terminus / Peptide ligand-binding receptors / calcium-mediated signaling / electron transport chain / sarcoplasmic reticulum / response to nicotine / cellular response to glucose stimulus / cell chemotaxis / neuropeptide signaling pathway / response to insulin / response to estrogen / chemotaxis / positive regulation of angiogenesis / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / synaptic vesicle membrane / cellular response to lipopolysaccharide / positive regulation of cytosolic calcium ion concentration / angiogenesis / adenylate cyclase-activating G protein-coupled receptor signaling pathway / signaling receptor activity / presynaptic membrane / chemical synaptic transmission / defense response to virus / G alpha (i) signalling events / response to ethanol / perikaryon / electron transfer activity / periplasmic space / cell surface receptor signaling pathway / postsynaptic membrane / cell adhesion / neuron projection / immune response / inflammatory response / iron ion binding / G protein-coupled receptor signaling pathway / 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 / membrane / plasma membrane / cytoplasm
Similarity search - Function
CXC chemokine receptor 3 / Kappa opioid receptor / Chemokine receptor family / Opioid receptor / : / 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 / Chemokine receptor family / Opioid receptor / : / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile.
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-
UpdateJul 23, 2025-
Current statusJul 23, 2025Processing 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

CTF correctionSoftware - Name: Gctf / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
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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