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TitleStructural insights into selective and dual antagonism of EP2 and EP4 prostaglandin receptors.
Journal, issue, pagesEMBO J, Vol. 44, Issue 23, Page 7242-7262, Year 2025
Publish dateOct 29, 2025
AuthorsYanli Wu / Heng Zhang / Jiuyin Xu / Kai Wu / Wen Hu / Xinheng He / Gaoming Wang / Canrong Wu / H Eric Xu /
PubMed AbstractProstaglandin 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.
External linksEMBO J / PubMed:41162752 / PubMed Central
MethodsEM (single particle)
Resolution2.65 - 3.5 Å
Structure data

61743

9jqy

EMDB-61743, PDB-9jqy:
Structural Insights into Selective Antagonism of TG6-129 and EP4 Prostaglandin Receptor
Method: EM (single particle) / Resolution: 2.92 Å

61744

9jqz

EMDB-61744, PDB-9jqz:
Structural Insights into Selective Antagonism Grapiprant and EP4 Prostaglandin Receptor
Method: EM (single particle) / Resolution: 2.65 Å

61762

9jro

EMDB-61762, PDB-9jro:
Structural Insights into Selective Antagonism of PF04418948 and EP2 Prostaglandin Receptor
Method: EM (single particle) / Resolution: 3.5 Å

61763

9jrt

EMDB-61763, PDB-9jrt:
Structural Insights into Selective Antagonism of TG6-129 and EP2 Prostaglandin Receptor
Method: EM (single particle) / Resolution: 3.28 Å

Chemicals

PDB-1ec5:
CRYSTAL STRUCTURE OF FOUR-HELIX BUNDLE MODEL

ChemComp-HOH:
WATER

PDB-1ecr:
ESCHERICHIA COLI REPLICATION TERMINATOR PROTEIN (TUS) COMPLEXED WITH DNA

PDB-1ecs:
THE 1.7 A CRYSTAL STRUCTURE OF A BLEOMYCIN RESISTANCE DETERMINANT ENCODED ON THE TRANSPOSON TN5

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • synthetic construct (others)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / GPCR / MEMBRANE PROTEIN-IMMUNE SYSTEM complex

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