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- EMDB-38803: Structure of CXCR3 in complex with VUF11418 (Receptor-ligand focu... -

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Basic information

Entry
Database: EMDB / ID: EMD-38803
TitleStructure of CXCR3 in complex with VUF11418 (Receptor-ligand focused map)
Map data
Sample
  • Complex: C-X-C chemokine receptor type 3 in complex with VUF11418
    • Protein or peptide: C-X-C chemokine receptor type 3
  • Ligand: [(1~{R},5~{S})-6,6-dimethyl-2-bicyclo[3.1.1]hept-2-enyl]methyl-[[4-(2-iodanylphenyl)phenyl]methyl]-dimethyl-azanium
KeywordsGPCR / Arrestin / SIGNALING PROTEIN
Function / homology
Function and homology information


regulation of leukocyte migration / chemokine binding / C-X-C chemokine binding / chemokine receptor activity / C-X-C chemokine receptor activity / C-C chemokine receptor activity / positive regulation of chemotaxis / C-C chemokine binding / negative regulation of execution phase of apoptosis / Chemokine receptors bind chemokines ...regulation of leukocyte migration / chemokine binding / C-X-C chemokine binding / chemokine receptor activity / C-X-C chemokine receptor activity / C-C chemokine receptor activity / positive regulation of chemotaxis / C-C chemokine binding / negative regulation of execution phase of apoptosis / Chemokine receptors bind chemokines / negative regulation of endothelial cell proliferation / positive regulation of execution phase of apoptosis / regulation of cell adhesion / positive regulation of release of sequestered calcium ion into cytosol / negative regulation of angiogenesis / cell chemotaxis / calcium-mediated signaling / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of angiogenesis / chemotaxis / signaling receptor activity / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / angiogenesis / cell surface receptor signaling pathway / cell adhesion / immune response / G protein-coupled receptor signaling pathway / inflammatory response / external side of plasma membrane / apoptotic process / positive regulation of cell population proliferation / cell surface / positive regulation of transcription by RNA polymerase II / plasma membrane / cytoplasm
Similarity search - Function
CXC chemokine receptor 3 / Chemokine receptor family / : / 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
C-X-C chemokine receptor type 3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.53 Å
AuthorsSano FK / Saha S / Sharma S / Ganguly M / Shihoya W / Nureki O / Shukla AK / Banerjee R
Funding support India, 1 items
OrganizationGrant numberCountry
Science and Engineering Research Board (SERB)IPA/2020/000405 India
CitationJournal: Nat Commun / Year: 2025
Title: Structural visualization of small molecule recognition by CXCR3 uncovers dual-agonism in the CXCR3-CXCR7 system.
Authors: Shirsha Saha / Fumiya K Sano / Saloni Sharma / Manisankar Ganguly / Annu Dalal / Sudha Mishra / Divyanshu Tiwari / Hiroaki Akasaka / Takaaki A Kobayashi / Nabarun Roy / Nashrah Zaidi / ...Authors: Shirsha Saha / Fumiya K Sano / Saloni Sharma / Manisankar Ganguly / Annu Dalal / Sudha Mishra / Divyanshu Tiwari / Hiroaki Akasaka / Takaaki A Kobayashi / Nabarun Roy / Nashrah Zaidi / Yuzuru Itoh / Rob Leurs / Ramanuj Banerjee / Wataru Shihoya / Osamu Nureki / Arun K Shukla /
Abstract: Chemokine receptors are critically involved in multiple physiological and pathophysiological processes related to immune response mechanisms. Most chemokine receptors are prototypical GPCRs although ...Chemokine receptors are critically involved in multiple physiological and pathophysiological processes related to immune response mechanisms. Most chemokine receptors are prototypical GPCRs although some also exhibit naturally-encoded signaling-bias toward β-arrestins (βarrs). C-X-C type chemokine receptors, namely CXCR3 and CXCR7, constitute a pair wherein the former is a prototypical GPCR while the latter exhibits selective coupling to βarrs despite sharing a common natural agonist: CXCL11. Moreover, CXCR3 and CXCR7 also recognize small molecule agonists suggesting a modular orthosteric ligand binding pocket. Here, we determine cryo-EM structures of CXCR3 in an Apo-state and in complex with small molecule agonists biased toward G-proteins or βarrs. These structural snapshots uncover an allosteric network bridging the ligand-binding pocket to intracellular side, driving the transducer-coupling bias at this receptor. Furthermore, structural topology of the orthosteric binding pocket also allows us to discover and validate that selected small molecule agonists of CXCR3 display robust agonism at CXCR7. Collectively, our study offers molecular insights into signaling-bias and dual agonism in the CXCR3-CXCR7 system with therapeutic implications.
History
DepositionJan 22, 2024-
Header (metadata) releaseFeb 26, 2025-
Map releaseFeb 26, 2025-
UpdateApr 9, 2025-
Current statusApr 9, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38803.png

Downloads & links

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Map

FileDownload / File: emd_38803.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesX (Sec.)Y (Row.)Z (Col.)
1.04 Å/pix.
x 240 pix.
= 249. Å		1.04 Å/pix.
x 240 pix.
= 249. Å		1.04 Å/pix.
x 240 pix.
= 249. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0375 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 7.0
Minimum - Maximum-31.314959000000002 - 56.690033
Average (Standard dev.)0.000000000011213 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 249.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_38803_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_38803_half_map_2.map
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Sample components

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Entire : C-X-C chemokine receptor type 3 in complex with VUF11418

EntireName: C-X-C chemokine receptor type 3 in complex with VUF11418
Components
  • Complex: C-X-C chemokine receptor type 3 in complex with VUF11418
    • Protein or peptide: C-X-C chemokine receptor type 3
  • Ligand: [(1~{R},5~{S})-6,6-dimethyl-2-bicyclo[3.1.1]hept-2-enyl]methyl-[[4-(2-iodanylphenyl)phenyl]methyl]-dimethyl-azanium

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Supramolecule #1: C-X-C chemokine receptor type 3 in complex with VUF11418

SupramoleculeName: C-X-C chemokine receptor type 3 in complex with VUF11418
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: C-X-C chemokine receptor type 3

MacromoleculeName: C-X-C chemokine receptor type 3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.597906 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGKTIIALSY IFCLVFADYK DDDDAANFTP VNGSSGNQSV RLVTSSSLEV LFQGPGSVLE VSDHQVLNDA EVAALLENFS SSYDYGENE SDSCCTSPPC PQDFSLNFDR AFLPALYSLL FLLGLLGNGA VAAVLLSRRT ALSSTDTFLL HLAVADTLLV L TLPLWAVD ...String:
MGKTIIALSY IFCLVFADYK DDDDAANFTP VNGSSGNQSV RLVTSSSLEV LFQGPGSVLE VSDHQVLNDA EVAALLENFS SSYDYGENE SDSCCTSPPC PQDFSLNFDR AFLPALYSLL FLLGLLGNGA VAAVLLSRRT ALSSTDTFLL HLAVADTLLV L TLPLWAVD AAVQWVFGSG LCKVAGALFN INFYAGALLL ACISFDRYLN IVHATQLYRR GPPARVTLTC LAVWGLCLLF AL PDFIFLS AHHDERLNAT HCQYNFPQVG RTALRVLQLV AGFLLPLLVM AYCYAHILAV LLVSRGQRRL RAMRLVVVVV VAF ALCWTP YHLVVLVDIL MDLGALARNC GRESRVDVAK SVTSGLGYMH CCLNPLLYAF VGVKFRERMW MLLLRLGCPN QRGL QRQPS SSRRDSSWSE TSEASYSGL

UniProtKB: C-X-C chemokine receptor type 3

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Macromolecule #2: [(1~{R},5~{S})-6,6-dimethyl-2-bicyclo[3.1.1]hept-2-enyl]methyl-[[...

MacromoleculeName: [(1~{R},5~{S})-6,6-dimethyl-2-bicyclo[3.1.1]hept-2-enyl]methyl-[[4-(2-iodanylphenyl)phenyl]methyl]-dimethyl-azanium
type: ligand / ID: 2 / Number of copies: 1 / Formula: A1LW2
Molecular weightTheoretical: 472.425 Da

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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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.1 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.53 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4) / Number images used: 150213
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationSoftware - Name: cryoSPARC (ver. 4.4)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8y0h:
Structure of CXCR3 in complex with VUF11418 (Receptor-ligand focused map)

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