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TitleMolecular basis for ligand recognition and receptor activation of the prostaglandin D2 receptor DP1.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 122, Issue 22, Page e2501902122, Year 2025
Publish dateJun 3, 2025
AuthorsJiuyin Xu / Yanli Wu / Youwei Xu / Yang Li / Xinheng He / Heng Zhang / James Jiqi Wang / Jingjing Hou / Junrui Li / Wen Hu / Kai Wu / Qingning Yuan / Canrong Wu / H Eric Xu /
PubMed AbstractThe prostaglandin D2 receptor 1 (DP1), a rhodopsin-like Class A GPCR, orchestrates critical physiological and pathological processes, ranging from sleep regulation to inflammatory responses and ...The prostaglandin D2 receptor 1 (DP1), a rhodopsin-like Class A GPCR, orchestrates critical physiological and pathological processes, ranging from sleep regulation to inflammatory responses and cardiovascular function. Despite its therapeutic significance, structural insights into DP1 activation mechanisms have remained elusive. Here, using cryoelectron microscopy (cryo-EM), we determined high-resolution structures of human DP1 in both inactive and active states, with the latter captured in complex with its endogenous agonist PGD2 or the synthetic agonist BW245C, bound to the stimulatory G protein, Gs. Our structures, coupled with functional and mutagenesis studies, unveiled unique structural features of DP1, including an alternative activation mechanism, ligand-selectivity determinants, and G protein coupling characteristics. These molecular insights provide a rational framework for designing selective DP1-targeted therapeutics, both agonists and antagonists, with enhanced specificity and reduced off-target effects, opening broad avenues for treating DP1-associated disorders.
External linksProc Natl Acad Sci U S A / PubMed:40440061 / PubMed Central
MethodsEM (single particle)
Resolution2.35 - 3.41 Å
Structure data

EMDB-60513, PDB-8zvz:
Cryo-EM strcuture of Prostaglandin D2 Receptor DP1 activated by BW245C
Method: EM (single particle) / Resolution: 2.35 Å

EMDB-60514, PDB-8zw0:
Cryo-EM strcuture of Prostaglandin D2 Receptor DP1 activated by PGD2
Method: EM (single particle) / Resolution: 2.72 Å

EMDB-64550, PDB-9uwd:
Cryo-EM structure of inactive-DP1
Method: EM (single particle) / Resolution: 3.41 Å

Chemicals

PDB-1af8:
ACTINORHODIN POLYKETIDE SYNTHASE ACYL CARRIER PROTEIN FROM STREPTOMYCES COELICOLOR A3(2), NMR, 24 STRUCTURES

ChemComp-CLR:
CHOLESTEROL

ChemComp-HOH:
WATER

ChemComp-PG2:
PROSTAGLANDIN D2

Source
  • homo sapiens (human)
  • lama glama (llama)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / Prostaglandin / DP1 / BW245C / PGD2 / GPCR / inactive

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