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- PDB-8y0n: Structure of CXCR3 in complex with VUF11418 and Go (Full map) -

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Basic information

Entry
Database: PDB / ID: 8y0n
TitleStructure of CXCR3 in complex with VUF11418 and Go (Full map)
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Antibody fragment ScFv16
  • C-X-C chemokine receptor type 3
KeywordsSIGNALING PROTEIN/IMMUNE / GPCR / Arrestin / SIGNALING PROTEIN-IMMUNE SYSTEM complex / SIGNALING PROTEIN-IMMUNE complex
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 / mu-type opioid receptor binding / C-C chemokine receptor activity / corticotropin-releasing hormone receptor 1 binding / positive regulation of chemotaxis / C-C chemokine binding ...regulation of leukocyte migration / chemokine binding / C-X-C chemokine binding / chemokine receptor activity / C-X-C chemokine receptor activity / mu-type opioid receptor binding / C-C chemokine receptor activity / corticotropin-releasing hormone receptor 1 binding / positive regulation of chemotaxis / C-C chemokine binding / negative regulation of execution phase of apoptosis / vesicle docking involved in exocytosis / Chemokine receptors bind chemokines / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction / parallel fiber to Purkinje cell synapse / negative regulation of endothelial cell proliferation / positive regulation of execution phase of apoptosis / postsynaptic modulation of chemical synaptic transmission / regulation of cell adhesion / negative regulation of insulin secretion / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / muscle contraction / positive regulation of release of sequestered calcium ion into cytosol / negative regulation of angiogenesis / GABA-ergic synapse / cell chemotaxis / locomotory behavior / calcium-mediated signaling / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / positive regulation of angiogenesis / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / chemotaxis / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / signaling receptor activity / Thrombin signalling through proteinase activated receptors (PARs) / presynaptic membrane / G protein activity / cell body / GTPase binding / positive regulation of cytosolic calcium ion concentration / Ca2+ pathway / retina development in camera-type eye / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / angiogenesis / G alpha (q) signalling events / postsynaptic membrane / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / cell surface receptor signaling pathway / cell adhesion / immune response / G protein-coupled receptor signaling pathway / inflammatory response / external side of plasma membrane
Similarity search - Function
CXC chemokine receptor 3 / Chemokine receptor family / : / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit ...CXC chemokine receptor 3 / Chemokine receptor family / : / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / Guanine nucleotide-binding protein G(o) subunit alpha / C-X-C chemokine receptor type 3 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.07 Å
AuthorsSano, F.K. / Saha, S. / Sharma, S. / Ganguly, M. / Shihoya, W. / Nureki, O. / Shukla, A.K. / Banerjee, R.
Funding support India, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 26, 2025Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(o) subunit alpha
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
S: Antibody fragment ScFv16
R: C-X-C chemokine receptor type 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)146,9576
Polymers146,4845
Non-polymers4721
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#1: Protein Guanine nucleotide-binding protein G(o) subunit alpha


Mass: 27024.762 Da / Num. of mol.: 1 / Mutation: G42D,E43N,A227D,G230D,I332A,V335I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAO1 / Production host: Escherichia coli (E. coli) / References: UniProt: P09471
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38534.062 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Antibody / Protein / Non-polymers , 3 types, 3 molecules SR

#4: Antibody Antibody fragment ScFv16


Mass: 26466.486 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Escherichia coli (E. coli)
#5: Protein C-X-C chemokine receptor type 3 / CXC-R3 / CXCR-3 / CKR-L2


Mass: 46597.906 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CXCR3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P49682
#6: Chemical ChemComp-A1LW2 / [(1~{R},5~{S})-6,6-dimethyl-2-bicyclo[3.1.1]hept-2-enyl]methyl-[[4-(2-iodanylphenyl)phenyl]methyl]-dimethyl-azanium


Mass: 472.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H31IN / Feature type: SUBJECT OF INVESTIGATION

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Details

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 in complex with VUF11418 and Go / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 defocus max: 1600 nm / Nominal defocus min: 800 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50.1 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
7Cootmodel fitting
11cryoSPARC4.4classification
12cryoSPARC4.43D reconstruction
13PHENIXmodel refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.07 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 150213 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingSource name: AlphaFold / Type: in silico model

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