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- PDB-8xyi: Structure of CXCR3 in complex with VUF10661 (Receptor-ligand focu... -

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Basic information

Entry
Database: PDB / ID: 8xyi
TitleStructure of CXCR3 in complex with VUF10661 (Receptor-ligand focused map)
ComponentsC-X-C chemokine receptor type 3
KeywordsSIGNALING PROTEIN / GPCR / Arrestin
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 / positive regulation of chemotaxis / C-C chemokine receptor activity / T cell chemotaxis / C-C chemokine binding / negative regulation of execution phase of apoptosis ...regulation of leukocyte migration / chemokine binding / C-X-C chemokine binding / chemokine receptor activity / C-X-C chemokine receptor activity / positive regulation of chemotaxis / C-C chemokine receptor activity / T cell 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 / angiogenesis / G alpha (i) signalling events / cell surface receptor signaling pathway / cell adhesion / immune response / G protein-coupled receptor signaling pathway / inflammatory response / external side of plasma membrane / positive regulation of cell population proliferation / apoptotic process / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.16 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 19, 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
Revision 1.0Feb 26, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Apr 9, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
R: C-X-C chemokine receptor type 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,2432
Polymers46,5981
Non-polymers6451
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: 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
#2: Chemical ChemComp-A1LW1 / (3~{S})-~{N}-[(2~{S})-6-azanyl-1-(2,2-diphenylethylamino)-1-oxidanylidene-hexan-2-yl]-2-(4-oxidanylidene-4-phenyl-butanoyl)-3,4-dihydro-1~{H}-isoquinoline-3-carboxamide


Mass: 644.802 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C40H44N4O4 / Feature type: SUBJECT OF INVESTIGATION
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: Structure of CXCR3 in complex with VUF10661 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
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
19PHENIXmodel refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.16 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 116462 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingSource name: AlphaFold / Type: in silico model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0032371
ELECTRON MICROSCOPYf_angle_d0.5493231
ELECTRON MICROSCOPYf_dihedral_angle_d4.774367
ELECTRON MICROSCOPYf_chiral_restr0.034384
ELECTRON MICROSCOPYf_plane_restr0.006405

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