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Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
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G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
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Molecular basis for ligand recognition and receptor activation of the prostaglandin D2 receptor DP1.

Jiuyin Xu1,2, Yanli Wu1, Youwei Xu1

  • 1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Proceedings of the National Academy of Sciences of the United States of America
|May 29, 2025
PubMed
Summary

Structural insights into the prostaglandin D2 receptor 1 (DP1) were revealed using cryo-EM. This study uncovered unique activation mechanisms and ligand-binding features, aiding the development of targeted DP1 therapies.

Keywords:
drug designprostaglandin D2 receptor 1receptor activation

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • The prostaglandin D2 receptor 1 (DP1) is a Class A G protein-coupled receptor (GPCR) involved in crucial physiological and pathological processes.
  • Understanding DP1 structure and activation is vital for developing targeted therapeutics, but has been limited by a lack of high-resolution structural data.

Purpose of the Study:

  • To determine the high-resolution structures of human DP1 in inactive and active states.
  • To elucidate the molecular mechanisms underlying DP1 activation, ligand selectivity, and G protein coupling.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to resolve DP1 structures.
  • Functional and mutagenesis studies were conducted to validate structural findings.

Main Results:

  • High-resolution structures of human DP1 in inactive and active states were obtained.
  • Active state structures revealed complexes with agonists PGD2 or BW245C bound to the Gs protein.
  • Unique structural features, an alternative activation mechanism, ligand-selectivity determinants, and G protein coupling characteristics were identified.

Conclusions:

  • The determined DP1 structures provide unprecedented molecular insights into its activation and function.
  • These findings offer a rational basis for designing highly selective DP1-targeting drugs (agonists and antagonists).
  • This research opens new therapeutic avenues for DP1-associated conditions with improved specificity and reduced side effects.