Structure and pharmacology of GPR32 in the resolution of inflammation

项目摘要 炎症是一个复杂的过程，涉及多种脂质介质。这些调解人中有很大一部分是 二十烷基类脂类通过作用于G蛋白来促进促炎或促分解作用- 偶联受体(GPCRs)。这些二十烷基脂有很高的化学相似性。然而，他们的目标是 不同的GPCR可能通过诱导不同的信号通路在炎症中发挥不同的作用。 二十烷基类脂类信号的潜在机制在很大程度上是未知的。我们小组研究的是 二十烷基类GPCRs的重要家族，包括促炎二十烷基类脂类的受体 如前列腺素D2(PGD2)和特殊的促分解脂介质(SPM)，如脂氧素A4 (LXA4)和Resolvin D1(RvD1)，旨在了解配体识别的分子机制和 受体信号。我们首次发表了拮抗剂结合的DP2的结构作为PGD2的受体。 最近，我们获得了一个脂质结合的DP2的晶体结构和另一个受体的冷冻-EM结构 家族，FPR2/ALX，作为LXA4的受体。在这些进展的基础上，我们建议进一步研究该结构 GPR32作为解决素D1受体的药理作用。我们的目标是获得一个全面的结构 理解促拆分剂如何作用于GPR32并通过GPR32发出信号并使用结构信息 开发新的GPR32配体作为有用的研究工具和潜在的候选药物。在建议的 我们将建立实验系统，获取GPR32和GPR32信号复合体的样本 用于低温电子显微镜的结构表征。我们还将基于我们的 脂质结合的DP2的结构，并用它来预测新的GPR32配体。结果将提供一个坚实的 为我们未来在GPR32信号和基于结构的研究方面的努力奠定基础 作为新型前拆分剂的新型GPR32配体的开发。

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.