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- PDB-9jqy: Structural Insights into Selective Antagonism of TG6-129 and EP4 ... -

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Basic information

Entry
Database: PDB / ID: 9jqy
TitleStructural Insights into Selective Antagonism of TG6-129 and EP4 Prostaglandin Receptor
Components
  • GFP-like fluorescent chromoprotein,Prostaglandin E2 receptor EP4 subtype
  • Heavy chain of Fab fragment
  • Light chain of Fab fragment
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / GPCR / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


negative regulation of eosinophil extravasation / prostaglandin E receptor activity / negative regulation of integrin activation / Prostanoid ligand receptors / T-helper cell differentiation / regulation of stress fiber assembly / negative regulation of cytokine production / response to mechanical stimulus / JNK cascade / response to prostaglandin E ...negative regulation of eosinophil extravasation / prostaglandin E receptor activity / negative regulation of integrin activation / Prostanoid ligand receptors / T-helper cell differentiation / regulation of stress fiber assembly / negative regulation of cytokine production / response to mechanical stimulus / JNK cascade / response to prostaglandin E / ERK1 and ERK2 cascade / positive regulation of cytokine production / cellular response to mechanical stimulus / bone development / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / negative regulation of inflammatory response / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of inflammatory response / cellular response to prostaglandin E stimulus / positive regulation of cytosolic calcium ion concentration / G alpha (s) signalling events / immune response / inflammatory response / membrane / plasma membrane
Similarity search - Function
Prostanoid EP4 receptor / Prostaglandin DP receptor / Prostanoid receptor / 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
: / Prostaglandin E2 receptor EP4 subtype
Similarity search - Component
Biological speciesMus musculus (house mouse)
synthetic construct (others)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.92 Å
AuthorsWu, Y.L. / Zhang, H. / Xu, J.Y. / Wu, C.R. / Xu, E.H.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: EMBO J / Year: 2025
Title: Structural insights into selective and dual antagonism of EP2 and EP4 prostaglandin receptors.
Authors: Yanli Wu / Heng Zhang / Jiuyin Xu / Kai Wu / Wen Hu / Xinheng He / Gaoming Wang / Canrong Wu / H Eric Xu /
Abstract: Prostaglandin E2 (PGE2) signaling through EP2 and EP4 receptors is crucial in regulating inflammation, pain, and cancer progression. While selective and dual antagonists for these receptors hold ...Prostaglandin E2 (PGE2) signaling through EP2 and EP4 receptors is crucial in regulating inflammation, pain, and cancer progression. While selective and dual antagonists for these receptors hold therapeutic potential, their binding mechanisms and selectivity have remained unclear. In this study, we present cryo-electron microscopy (cryo-EM) structures of human EP2 and EP4 receptors in complex with selective antagonists PF-04418948 and grapiprant, as well as with the dual antagonist TG6-129. These structures reveal distinct binding pockets and interaction networks that dictate antagonist selectivity and efficacy. Notably, TG6-129 displays a novel binding mode, engaging deeply with EP2 while interacting more superficially with EP4 in a two-warhead manner. Furthermore, comparisons of active and inactive receptor structures elucidate the mechanisms underlying EP2 activation and antagonism. Overall, these findings provide a structural framework for understanding prostanoid receptor pharmacology and offer valuable insights for the rational design of improved selective and dual antagonists targeting EP2 and EP4 receptors.
History
DepositionSep 28, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Oct 22, 2025Provider: repository / Type: Initial release
Revision 1.0Oct 22, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Oct 22, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Oct 22, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 22, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 22, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 22, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Nov 12, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
H: Heavy chain of Fab fragment
L: Light chain of Fab fragment
A: GFP-like fluorescent chromoprotein,Prostaglandin E2 receptor EP4 subtype
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,4764
Polymers117,9823
Non-polymers4941
Water1086
1


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

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Components

#1: Antibody Heavy chain of Fab fragment


Mass: 27574.092 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#2: Antibody Light chain of Fab fragment


Mass: 28944.303 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#3: Protein GFP-like fluorescent chromoprotein,Prostaglandin E2 receptor EP4 subtype / prostaglandin E receptor EP4 / PGE receptor EP4 subtype / PGE2 receptor EP4 subtype / Prostanoid EP4 receptor


Mass: 61463.859 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others), (gene. exp.) Homo sapiens (human)
Gene: PTGER4, PTGER2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P35408
#4: Chemical ChemComp-A1EC5 / ~{N}-[[4-[(5-ethyl-1,3,4-thiadiazol-2-yl)sulfamoyl]phenyl]carbamothioyl]-3-(4-fluorophenyl)propanamide


Mass: 493.598 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20FN5O3S3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: H2O
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: human prostaglandin E receptor EP4 / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Mus musculus (house mouse)10090
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.3
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: DIFFRACTION / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.92 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 97395 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0025480
ELECTRON MICROSCOPYf_angle_d0.4027466
ELECTRON MICROSCOPYf_dihedral_angle_d9.8081929
ELECTRON MICROSCOPYf_chiral_restr0.037861
ELECTRON MICROSCOPYf_plane_restr0.004920

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