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- PDB-9jro: Structural Insights into Selective Antagonism of PF04418948 and E... -

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Basic information

Entry
Database: PDB / ID: 9jro
TitleStructural Insights into Selective Antagonism of PF04418948 and EP2 Prostaglandin Receptor
Components
  • GFP-like fluorescent chromoprotein,Prostaglandin E2 receptor EP2 subtype,Soluble cytochrome b562,Prostaglandin E2 receptor EP2 subtype,Soluble cytochrome b562
  • Heavy chain of Fab fragment
  • Light chain of Fab fragment
  • Nb
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / GPCR / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


prostaglandin E receptor activity / Prostanoid ligand receptors / response to nematode / response to progesterone / electron transport chain / adenylate cyclase-activating G protein-coupled receptor signaling pathway / cellular response to prostaglandin E stimulus / regulation of cell population proliferation / positive regulation of cytosolic calcium ion concentration / response to lipopolysaccharide ...prostaglandin E receptor activity / Prostanoid ligand receptors / response to nematode / response to progesterone / electron transport chain / adenylate cyclase-activating G protein-coupled receptor signaling pathway / cellular response to prostaglandin E stimulus / regulation of cell population proliferation / positive regulation of cytosolic calcium ion concentration / response to lipopolysaccharide / G alpha (s) signalling events / periplasmic space / electron transfer activity / G protein-coupled receptor signaling pathway / iron ion binding / inflammatory response / heme binding / plasma membrane
Similarity search - Function
Prostanoid EP2 receptor / Prostanoid receptor / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 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
: / Soluble cytochrome b562 / Prostaglandin E2 receptor EP2 subtype
Similarity search - Component
Biological speciesMus musculus (house mouse)
synthetic construct (others)
Homo sapiens (human)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 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 29, 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
Revision 1.2Nov 26, 2025Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / em_admin ...chem_comp / em_admin / entity / pdbx_entity_nonpoly
Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _em_admin.last_update / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 2.0Nov 26, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Experimental summary / Structure summary / Data content type: EM metadata / EM metadata / Category: em_admin / entity
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata
Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _em_admin.last_update / _entity.pdbx_description

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: Heavy chain of Fab fragment
L: Light chain of Fab fragment
N: Nb
A: GFP-like fluorescent chromoprotein,Prostaglandin E2 receptor EP2 subtype,Soluble cytochrome b562,Prostaglandin E2 receptor EP2 subtype,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,9155
Polymers137,5064
Non-polymers4091
Water00
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: 24152.984 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: 23398.066 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 Nb


Mass: 13276.541 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Spodoptera frugiperda (fall armyworm)
#4: Protein GFP-like fluorescent chromoprotein,Prostaglandin E2 receptor EP2 subtype,Soluble cytochrome b562,Prostaglandin E2 receptor EP2 subtype,Soluble cytochrome b562 / PGE receptor EP2 subtype / PGE2 receptor EP2 subtype / Prostanoid EP2 receptor / Cytochrome b-562


Mass: 76678.398 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. exp.) Escherichia coli (E. coli)
Gene: PTGER2, cybC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P43116, UniProt: P0ABE7
#5: Chemical ChemComp-A1ECS / PF-04418948 / 1-(4-fluorophenyl)carbonyl-3-[(6-methoxynaphthalen-2-yl)oxymethyl]azetidine-3-carboxylic acid


Mass: 409.407 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H20FNO5 / 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: human prostaglandin E receptor EP2 / Type: COMPLEX / Entity ID: #4, #1-#3 / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Escherichia coli (E. coli)562
41Mus 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 software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 214366 / Symmetry type: POINT
RefinementStereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0017077
ELECTRON MICROSCOPYf_angle_d0.4129621
ELECTRON MICROSCOPYf_dihedral_angle_d17.082499
ELECTRON MICROSCOPYf_chiral_restr0.0361095
ELECTRON MICROSCOPYf_plane_restr0.0041208

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