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

In a study published in PNAS on December 12, 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, the researchers resolved structures of various DP2-Gi complexes at high resolutions, specifically ranging from 2.3 Å to 2.8 Å. A key finding of the study was identification of a phospholipid binding site at the DP2-G protein interface, which modulates interactions between DP2 and G proteins. This lipid regulation plays a crucial role in influencing the receptor's activation state and signaling outcomes. 

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 significance of this research extended beyond basic science, as it paved 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. This study was particularly relevant given the increasing prevalence of allergic diseases, such as asthma, which affect millions of people worldwide.

DOI: 10.1073/pnas.2403304121

Molecular Basis of Lipid and Ligand Regulation of the Prostaglandin Receptor DP2 and Its Signal Bias Mechanism. (Image by WU Canrong)

Contact:

JIANG Qingling

Shanghai Institute of Materia Medica, Chinese Academy of Sciences

E-mail: qljiang@stimes.cn