Structure and pharmacology of GPR32 in the resolution of inflammation

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Project Summary Inflammation is a complex process with many lipid mediators involved. A large number of these mediators are eicosanoid lipids that promote either pro-inflammatory or pro-resolving effects through action on G protein- coupled receptors (GPCRs). These eicosanoid lipids share a high chemical similarity. However, they target different GPCRs and elicit distinct roles in inflammation, potentially by inducing different signaling pathways. The mechanism underlying the signaling of eicosanoid lipids is largely unknown. Our group studies an important family of eicosanoid GPCRs that comprises receptors for both pro-inflammatory eicosanoid lipids such as prostaglandin D2 (PGD2) and specialized pro-resolving lipid mediators (SPMs) such as lipoxin A4 (LXA4) and resolvin D1 (RvD1), aiming to understand the molecular mechanisms for ligand recognition and receptor signaling. We published the first structures of antagonist-bound DP2 as the receptor for PGD2. Recently, we obtained a crystal structure of lipid-bound DP2 and a cryo-EM structure of another receptor in this family, FPR2/ALX, as the receptor for LXA4. Built on such progress, we propose to further study the structure and pharmacology of GPR32 as the receptor for resolvin D1. We aim to gain a comprehensive structural understanding of how pro-resolving agents act on and signal through GPR32 and use the structural information to develop novel GPR32 ligands as useful research tools and potential drug candidates. In the proposed initiatives, we will establish experimental systems to obtain samples of GPR32 and GPR32 signaling complex for structural characterization by cryo-EM. We will also obtain a structural model of GPR32 based on our structure of lipid-bound DP2 and use it to predict new GPR32 ligands. The results will provide a solid foundation for our future research efforts in the structural elucidation of GPR32 signaling and structure-based development of new GPR32 ligands as novel pro-resolving agents.