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Structure and pharmacology of GPR32 in the resolution of inflammation

GPR32 的结构和药理学在炎症消退中的作用

基本信息

批准号：
10217380
负责人：
CHENG ZHANG
金额：
$ 15.65万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217380
关键词：
ARNT gene Address Adopted Agonist Anti-Inflammatory Agents Binding Biological Assay Chemicals Complex Cryoelectron Microscopy Crystallization Development Disease Eicosanoids FPR2 gene Family Foundations Funding Future G-Protein-Coupled Receptors GPR32 gene Genome Homeostasis Inflammation Inflammatory Investigation Knowledge Ligands Lipid Binding Lipids Lipoxins Mediator of activation protein Modeling Molecular Mutagenesis Negative Staining Orphan Pharmaceutical Preparations Pharmacology Pharmacotherapy Phylogenetic Analysis Physiology Play Preparation Process Prostaglandin D2 Prostaglandin Receptor Prostaglandins Publishing Receptor Signaling Reporting Research Resolution Role Sampling Signal Pathway Signal Transduction Solid Structural Models Structure System Testing Therapeutic Tissues Viral Respiratory Tract Infection Work base combat cytokine release syndrome drug candidate drug development frontier improved lipid mediator lipoxin A4 novel novel drug class novel therapeutics programs receptor restoration structural biology success tool virtual screening

项目摘要

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.

项目摘要炎症是一个复杂的过程，涉及许多脂质介质。其中大量调解人是类二十烷酸脂质，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。类二十烷酸脂质信号传导的机制在很大程度上尚不清楚。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（PGD2）和专门的促分解脂质介质（SPM），例如脂氧素A4 （LXA 4）和resolvin D1（RvD1），旨在了解配体识别的分子机制，受体信号我们发表了作为PGD2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DP2的晶体结构和另一种受体的冷冻电镜结构。家族，FPR2/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GPR32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GPR32并通过GPR32发出信号，以及如何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。拟议我们将建立实验系统，以获得GPR32和GPR32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GPR32的基础上，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GPR32配体作为新的前拆分剂。