Structure and pharmacology of GPR32 in the resolution of inflammation

项目摘要 炎症是一个复杂的过程，涉及许多脂质介质。这些调解人中有许多是 类二十烷酸脂质，通过作用于G蛋白促进促炎或促消退作用， 偶联受体（GPCR）。这些类二十烷酸脂质具有高度的化学相似性。然而，他们的目标 不同的GPCR并可能通过诱导不同的信号传导途径在炎症中引起不同的作用。 类二十烷酸脂质的信号转导机制在很大程度上是未知的。我们小组研究了 类二十烷酸GPCR的重要家族，其包含促炎类二十烷酸脂质 例如前列腺素D2（PGD 2）和专门的促分解脂质介质（SPM），例如脂氧素A4 （LXA 4）和resolvin D1（RvD 1），旨在了解配体识别的分子机制， 受体信号我们发表了作为PGD 2受体的拮抗剂结合的DP 2的第一个结构。 最近，我们获得了脂质结合的DP 2的晶体结构和另一种受体的冷冻电镜结构。 家族，FPR 2/ALX，作为LXA 4的受体。在这些进展的基础上，我们建议进一步研究 以及GPR 32作为消退素D1受体的药理学。我们的目标是获得一个全面的结构 了解促分解剂如何作用于GPR 32并通过GPR 32发出信号，以及如何使用结构信息 开发新的GPR 32配体作为有用的研究工具和潜在的候选药物。拟议 我们将建立实验系统，以获得GPR 32和GPR 32信号复合物的样品， 用冷冻电镜进行结构表征。我们还将获得一个结构模型的GPR 32的基础上，我们的 脂质结合的DP 2的结构，并用它来预测新的GPR 32配体。结果将提供一个坚实的 为我们未来在GPR 32信号传导的结构解析和基于结构的研究工作奠定了基础。 开发新的GPR 32配体作为新的前拆分剂。

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.