Recent advancements in understanding molecular basis of the prostaglandin D₂ receptor (DP2) have significant implications for developing new anti-inflammatory and anti-allergic therapeutics. DP2, as a G protein-coupled receptor, plays a crucial role in mediating allergic responses and inflammation. However, the clinical application of several DP2-targeted drugs remains limited. 

In a study published in PNAS, 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 presented cryo-electron microscopy (cryo-EM) structures of apo DP2-Gi complex, a DP2-Gi complex bound to endogenous ligand PGD2, and a DP2-Gi complex bound to indomethacin, a ligand known to favor β-arrestin signaling. These structures revealed distinct binding modes and provided critical insights into the receptor's activation and signaling bias, highlighting the role of lipid interactions.

Using advanced cryo-EM techniques, researchers resolved the structures of various DP2-Gi complexes at high resolutions, specifically ranging from 2.3 Å to 2.8 Å. They identified a phospholipid binding site at the DP2-G protein interface, which modulates interactions between DP2 and G proteins. This lipid regulation played a crucial role in influencing the receptor's activation state and signaling outcomes. 

Besides, researchers found that PGD2 primarily activates DP2 through Gαi signaling pathway, while indomethacin preferentially activates the β-arrestin pathway. This signaling bias was further elucidated through functional assays and molecular dynamics simulations, demonstrating the unique pharmacological profiles of both ligands.

The study paves the way for rational design of safer and more effective anti-allergy drugs. By understanding how lipid interactions regulate DP2 activity, researchers can develop targeted therapies that minimize side effects.