Structure, pharmacology and signaling of G protein-coupled receptors (GPCRs) in inflammation

炎症中 G 蛋白偶联受体 (GPCR) 的结构、药理学和信号传导

• 批准号: 10453592
• 负责人: CHENG ZHANG
• 金额: $ 39.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453592
• 关键词: Agonist; Anaphylatoxins; Anti-Inflammatory Agents; Antibodies; Binding; Biology; C5a anaphylatoxin receptor; Chemicals; Complex; Crystallization; Crystallography; Development; Disease; Dopamine D2 Receptor; Drug Design; Electron Microscopy; FPR2 gene; Family; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Goals; Health; Inflammation; Inflammation Mediators; Inflammatory; Knowledge; Ligands; Lipids; Mediating; Mediator of activation protein; Molecular; Molecular Conformation; New Agents; Peptides; Pharmacologic Actions; Pharmacology; Phylogenetic Analysis; Process; Prostaglandin D2; Proteins; Receptor Activation; Receptor Signaling; Reporting; Research; Resolution; Signal Pathway; Structure; Targeted Research; Testing; Therapeutic; antagonist; base; clinical investigation; drug development; extracellular; innovation; lipid mediator; lipoxin A4; member; novel; novel therapeutics; receptor; receptor function; response; scaffold; small molecule; targeted agent; tool

Project Summary Inflammation is a complex process with many lipid and peptide mediators involved. A large number of these mediators elicit either pro-inflammatory or pro-resolving effects through the action on G protein-coupled receptors (GPCRs). Our research is focused on a group of GPCRs as close phylogenetic neighbors, which comprises receptors for the pro-inflammatory mediators including anaphylatoxins, formylpeptides and prostaglandin D2 (PGD2), and the newly discovered specialized pro-resolving lipid mediators (SPMs) including lipoxin A4 (LXA4) and resolvins. The members of this GPCR family are active targets for developing new drugs for a variety of inflammatory diseases. So far no structures have been reported for this family. Thus our understanding of the molecular mechanisms underlying ligand action, receptor activation and signaling is quite limited, which has impeded drug development. To fill this knowledge gap, recently we have obtained crystal structures of two members in this family, the C5a receptor (C5aR) and the prostaglandin D2 receptor 2 (CRTH2). These two structures provided innovative information regarding the antagonism of C5aR and CRTH2. We propose to further define the molecular determinants for the diverse pharmacological action of C5aR and CRTH2 antagonists by testing novel hypotheses based our structures. We will take protein crystallography and electron microscopy (EM) approaches in parallel to obtain high-resolution structures of active C5aR and CRTH2 in complex with agonists and the Gi protein. The results will reveal the structural basis of agonist binding and receptor activation. In addition, we propose to develop small-molecule antagonists with new chemical scaffolds for C5aR and CRTH2 through structure-based drug design (SBDD) approach. We will also test the possibility of developing extracellular conformational antibodies of C5aR and CRTH2 as new pharmacological tools to block pro-inflammatory signaling pathways. The long-term goal is to move towards the clinical investigation of such new agents for C5aR and CRTH2. Another long-term research direction is to study GPCRs that mediate pro-resolving signaling pathways to promote inflammation resolution. FPR2/ALX (formylpeptide receptor 2/LXA4 receptor) will be our primary research target. FPR2/ALX can be targeted by a number of structurally unrelated mediators to mediate either pro-inflammatory or pro-resolving responses. Research on this receptor is aimed to reveal the structural basis for the action of diverse ligands and the molecular mechanism for the functional selectivity. Our study is significant for health because the discoveries will facilitate the development of innovative pharmacological tools for both anti-inflammatory and pro-resolving therapeutic strategies in the treatment of many inflammatory diseases.

项目概要 炎症是一个复杂的过程，涉及许多脂质和肽介质。其中大量 介质通过作用于 G 蛋白偶联而引发促炎或促消退作用 受体（GPCR）。我们的研究重点是一组作为系统发育近邻的 GPCR，它们 包含促炎介质的受体，包括过敏毒素、甲酰肽和 前列腺素 D2 (PGD2) 和新发现的专门促溶解脂质介质 (SPM)，包括 脂氧素 A4 (LXA4) 和分解素。该 GPCR 家族的成员是开发新药的积极目标 用于多种炎症性疾病。到目前为止，还没有关于这个家庭的结构的报道。因此我们的 对配体作用、受体激活和信号转导的分子机制的了解相当深入 有限，这阻碍了药物开发。为了填补这一知识空白，最近我们获得了水晶 该家族两个成员的结构：C5a 受体 (C5aR) 和前列腺素 D2 受体 2 （CRTH2）。这两种结构提供了有关 C5aR 和 C5aR 拮抗作用的创新信息。 CRTH2。我们建议进一步定义多种药理作用的分子决定因素 通过测试基于我们的结构的新假设来开发 C5aR 和 CRTH2 拮抗剂。我们将摄入蛋白质 晶体学和电子显微镜（EM）方法并行以获得高分辨率结构 活性 C5aR 和 CRTH2 与激动剂和 Gi 蛋白形成复合物。结果将揭示结构 激动剂结合和受体激活的基础。此外，我们建议开发小分子拮抗剂 通过基于结构的药物设计 (SBDD) 方法使用 C5aR 和 CRTH2 的新化学支架。我们 还将测试开发C5aR和CRTH2胞外构象抗体作为新的可能性 阻断促炎信号通路的药理学工具。长期目标是朝着 针对 C5aR 和 CRTH2 的此类新药物的临床研究。另一个长期研究方向是 研究介导促消退信号通路以促进炎症消退的 GPCR。 FPR2/ALX （甲酰肽受体2/LXA4受体）将是我们的首要研究目标。 FPR2/ALX 可以被靶向 介导促炎症或促消退反应的结构上不相关的介质的数量。 对该受体的研究旨在揭示不同配体作用的结构基础以及 功能选择性的分子机制。我们的研究对健康具有重要意义，因为这些发现 将促进抗炎和促消退的创新药理学工具的开发 治疗许多炎症性疾病的治疗策略。