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- PDB-8hnn: Structure of CXCR3 complexed with antagonist SCH546738 -

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Basic information

Entry
Database: PDB / ID: 8hnn
TitleStructure of CXCR3 complexed with antagonist SCH546738
Components
  • Nb6
  • Soluble cytochrome b562,C-X-C chemokine receptor type 3,Kappa-type opioid receptor
KeywordsSIGNALING PROTEIN / G protein coupled receptor / chemokine receptor / CXCR3 / SCH546738 / complex
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 / chemokine binding / positive regulation of eating behavior / G protein-coupled opioid receptor activity ...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 / chemokine binding / positive regulation of eating behavior / G protein-coupled opioid receptor activity / C-X-C chemokine binding / chemokine receptor activity / G protein-coupled opioid receptor signaling pathway / C-X-C chemokine receptor activity / positive regulation of dopamine secretion / positive regulation of chemotaxis / sensory perception / C-C chemokine receptor activity / T cell chemotaxis / maternal behavior / positive regulation of potassium ion transmembrane transport / C-C chemokine binding / receptor serine/threonine kinase binding / neuropeptide binding / negative regulation of execution phase of apoptosis / positive regulation of p38MAPK cascade / Chemokine receptors bind chemokines / eating behavior / negative regulation of endothelial cell proliferation / conditioned place preference / positive regulation of execution phase of apoptosis / neuropeptide signaling pathway / estrous cycle / regulation of cell adhesion / MECP2 regulates neuronal receptors and channels / behavioral response to cocaine / axon terminus / sensory perception of pain / T-tubule / Peptide ligand-binding receptors / positive regulation of release of sequestered calcium ion into cytosol / negative regulation of angiogenesis / sarcoplasmic reticulum / cell chemotaxis / response to nicotine / locomotory behavior / cellular response to glucose stimulus / calcium-mediated signaling / electron transport chain / response to insulin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / response to estrogen / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of angiogenesis / chemotaxis / synaptic vesicle membrane / signaling receptor activity / cellular response to lipopolysaccharide / positive regulation of cytosolic calcium ion concentration / presynaptic membrane / response to ethanol / angiogenesis / perikaryon / G alpha (i) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / defense response to virus / chemical synaptic transmission / postsynaptic membrane / periplasmic space / electron transfer activity / cell surface receptor signaling pathway / cell adhesion / neuron projection / immune response / G protein-coupled receptor signaling pathway / iron ion binding / inflammatory response / external side of plasma membrane / positive regulation of cell population proliferation / apoptotic process / heme binding / dendrite / cell surface / positive regulation of transcription by RNA polymerase II / mitochondrion / nucleoplasm / membrane / plasma membrane / cytoplasm / cytosol
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
Chem-43I / CHOLESTEROL / Soluble cytochrome b562 / Kappa-type opioid receptor / C-X-C chemokine receptor type 3
Similarity search - Component
Biological speciesLama glama (llama)
Escherichia coli (E. coli)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsJiao, H.Z. / Hu, H.L.
Funding support China, 1items
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, 2022Deposition site: PDBJ / Processing site: PDBC
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
N: Nb6
R: Soluble cytochrome b562,C-X-C chemokine receptor type 3,Kappa-type opioid receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8724
Polymers74,9932
Non-polymers8792
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Antibody Nb6


Mass: 18665.906 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Spodoptera frugiperda (fall armyworm)
#2: Protein Soluble cytochrome b562,C-X-C chemokine receptor type 3,Kappa-type opioid receptor / Cytochrome b-562 / CXC-R3 / CXCR-3 / CKR-L2 / G protein-coupled receptor 9 / Interferon-inducible ...Cytochrome b-562 / CXC-R3 / CXCR-3 / CKR-L2 / G protein-coupled receptor 9 / Interferon-inducible protein 10 receptor / IP-10 receptor / K-OR-1 / KOR-1


Mass: 56327.051 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human)
Gene: cybC, CXCR3, GPR9, OPRK1, OPRK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P0ABE7, UniProt: P49682, UniProt: P41145
#3: Chemical ChemComp-43I / 3-azanyl-6-chloranyl-5-[(3S)-4-[1-[(4-chlorophenyl)methyl]piperidin-4-yl]-3-ethyl-piperazin-1-yl]pyrazine-2-carboxamide


Mass: 492.445 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H31Cl2N7O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O
Has ligand of interestY
Has protein modificationY

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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: CXCR3-KOR-SCH546738-Nb6 / Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 %

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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 / Nominal magnification: 105000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 1500 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Image recordingElectron dose: 53.43 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameCategory
4GctfCTF correction
8PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 509297 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0042466
ELECTRON MICROSCOPYf_angle_d0.8343369
ELECTRON MICROSCOPYf_dihedral_angle_d9.659369
ELECTRON MICROSCOPYf_chiral_restr0.119405
ELECTRON MICROSCOPYf_plane_restr0.006405

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