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.

项目摘要 炎症是一个复杂的过程，其中许多脂质和肽介质涉及。其中大量 介体通过对G蛋白偶联的作用引起促炎或促促疾病的效果 受体（GPCR）。我们的研究集中在一组GPCR上，作为紧密的系统发育邻国，这是 包括促炎性介质的受体，包括过敏毒素，甲基肽和 Prostaglandin D2（PGD2），以及新发现的专业培养脂质介质（SPM） Lipoxin A4（LXA4）和溶质。该GPCR家族的成员是开发新药的积极目标 用于各种炎症性疾病。到目前为止，尚未报告该家庭的结构。因此我们 了解配体作用，受体激活和信号传导的分子机制的理解非常 有限，这阻碍了药物开发。为了填补这一知识空白，最近我们获得了晶体 该家族两个成员的结构，C5A受体（C5AR）和前列腺素D2受体2 （CRTH2）。这两个结构提供了有关C5AR和的拮抗作用的创新信息 CRTH2。我们建议进一步定义分子决定因素 C5AR和CRTH2拮抗剂通过基于我们的结构测试新假设。我们将服用蛋白质 晶体学和电子显微镜（EM）的方法并联，以获得高分辨率结构 活性C5AR和CRTH2与激动剂和GI蛋白的复合物中。结果将揭示结构 激动剂结合和受体激活的基础。此外，我们建议发展小分子拮抗剂 通过基于结构的药物设计（SBDD）方法，采用了C5AR和CRTH2的新化学支架。我们 还将测试开发C5AR和CRTH2的细胞外构象抗体的可能性 阻止促炎信号通路的药理工具。长期目标是朝着 对C5AR和CRTH2的这种新药物的临床研究。另一个长期研究方向是 研究介导促促炎的信号通路以促进炎症解决方案的GPCR。 FPR2/ALX （甲基肽受体2/LXA4受体）将是我们的主要研究目标。 FPR2/ALX可以由 结构无关的介体的数量，以介导促炎或促疾病反应。 对该受体的研究旨在揭示各种配体和该受体作用的结构基础和 功能选择性的分子机制。我们的研究对健康意义重大，因为这些发现 将有助于开发用于抗炎和促进的创新药理学工具 治疗许多炎症性疾病的治疗策略。