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，其中许多脂质介质涉及。这些调解人中有很多通过对G蛋白 - 耦合受体（GPCR）。这些类固醇脂质具有很高的化学相似性。但是，他们针对的不同的GPCR并在炎症中引起不同的作用，可能通过诱导不同的信号通路。类花生酸脂质信号的基础机制在很大程度上尚不清楚。我们的小组研究 eicosanaid GPCR的重要家族，包括两种促炎类花生酸酯脂质的受体例如前列腺素D2（PGD2）和专门的促脂脂质介质（SPM），例如脂氧蛋白A4 （LXA4）和Resolvin D1（RVD1），旨在了解配体识别和受体信号传导。我们发表了拮抗剂结合DP2作为PGD2的受体的第一个结构。最近，我们获得了脂质结合DP2的晶体结构和另一个受体的冷冻EM结构 family，fpr2/alx，作为LXA4的受体。基于这样的进步，我们建议进一步研究结构 GPR32的药理学作为Resolvin D1的受体。我们的目标是获得全面的结构了解促进分辨的代理如何通过GPR32采用和发信号并使用结构信息开发新型GPR32配体作为有用的研究工具和潜在的候选药物。在提议中倡议，我们将建立实验系统，以获取GPR32和GPR32信号复合物的样品用于冷冻EM的结构表征。我们还将基于我们的GPR32的结构模型脂质结合DP2的结构，并使用它来预测新的GPR32配体。结果将提供坚实的我们未来研究工作的基础，用于阐明GPR32信号传导和基于结构的研究开发新的GPR32配体作为新颖的促剂剂。