Recent breakthroughs in understanding the prostaglandin D2 (PGD2) receptor 1 (DP1) are paving the way for innovative anti-inflammatory and immunomodulatory therapies.
DP1, a G protein-coupled receptor (GPCR), plays a key role in mediating allergic responses and inflammation. Although several DP1-targeting compounds have been identified, their clinical uses have been limited by the lack of detailed molecular understanding.
In a study published in PNAS on May 29, a research team led by Eric H. Xu (XU Huaqiang) and WU Canrong from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences unveiled high-resolution structures of human DP1.
Using advanced cryo-EM techniques, researchers determined the structures of the DP1 receptor in both its inactive and active states. The active state was resolved in two forms: one in complex with the natural agonist PGD2 and the stimulatory G protein Gs at a resolution of 2.72 Å, and the other with the synthetic agonist BW245C and Gs at a resolution of 2.35 Å. The inactive state was determined at a resolution of 3.41 Å.
These structures, combined with functional and mutagenesis studies, revealed unique features of DP1, including an alternative activation mechanism, determinants of ligand selectivity, and characteristics of G protein coupling.
Notably, researcher found that DP1 lacks the conserved W6.48 activation switch and the typical D/ERY motif that is usually involved in GPCR activation, indicating that its activation mechanism is rather unique and not a conserved mechanism.
These molecular insights not only complete the structural framework of PGD2 signaling through its receptor family, but also provide a detailed blueprint for designing selective DP1-targeted drugs-both agonists and antagonists-with greater precision and fewer off-target effects.
This work paves the way for new therapeutic strategies to treat inflammatory and allergic disorders linked to DP1.
