Structural Basis and Molecular Mechanism of GPCR-Arrestin Interactions

GPCR-Arrestin 相互作用的结构基础和分子机制

• 批准号: 10713322
• 负责人: Qiuyan Chen
• 金额: $ 39.63万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713322
• 关键词: Arrestins; Binding; Calcium; Cells; Complex; Cryoelectron Microscopy; Dissection; Drug Design; Drug Targeting; G Protein-Coupled Receptor Signaling; G protein coupled receptor kinase; G-Protein-Coupled Receptors; GTP-Binding Proteins; Hormones; Human; Immune response; Intervention; Ions; Mediating; Molecular; Moods; Neurotransmitters; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Photons; Physiological Processes; Publishing; Reporting; Resolution; Safety; Signal Pathway; Signal Transduction; Structure; Taste Perception; Therapeutic; Transducers; Vision; Visualization; blood pressure regulation; chemokine receptor; design; genetic regulatory protein; insight; novel; protein complex; receptor binding; receptor function; response; tool

Project Summary/Abstract G protein coupled receptors are essentially the molecular messengers of the cell, transducing signals from outside to inside. The signals are remarkably diverse, including a single photon, ion like calcium, neurotransmitters and hormones. Humans have more than 800 GPCRs for recognizing different signals, but only three types of transducers, G proteins, GPCR kinases (GRKs) and arrestins. GRKs phosphorylate GPCRs whereas G proteins and arrestins directly bind GPCRs, send the signal to downstream effectors and cause a cellular response. Comparing structures of GPCR bound to G protein and arrestin will provide valuable insights into the functional selectivity and guide the design of more potent drugs with better safety profiles. There are currently >300 structures of GPCR−G protein complex reported but only 8 published structures of GPCR−arrestin complex, which highlights the relative difficulty in obtaining suitable arrestin complexes for structural analysis. My lab focuses on the understudied GPCR−arrestin signaling pathway. We have developed a novel tool which stabilizes GPCR−arrestin complexes for cryo-electron microscopy studies and used that to visualize how the atypical chemokine receptor 3 engages arrestins in various ways at near-atomic resolution. For the next five years, we plan to expand the study to many important GPCR−arrestin pairs to understand the structural details to aid the design of selective interventions. This study will open the way to a detailed dissection of the mechanism of arrestin-mediated GPCR signaling but also to structure-based drug design.

项目摘要/摘要 G蛋白偶联受体本质上是细胞的分子信使， 从外部到内部传递信号。这些信号非常出色，其中包括一个 光子，像钙，神经递质和激素一样的离子。人类有800多个GPCR 用于识别不同的信号，但只有三种类型的传感器，G蛋白，GPCR激酶 （grks）和逮捕。 GRKS磷酸化GPCR，而G蛋白和阻止蛋白直接 结合GPCR，将信号发送到下游效应并引起细胞反应。比较 与G蛋白结合的GPCR结构和逮捕蛋白将提供有价值的见解 功能选择性并指导具有更好安全概况的更多潜在药物的设计。那里 目前，GPCR-G蛋白复合物的300个结构报道了，但只有8个发表 GPCR-arrestin复合物的结构，该结构突出了获得合适的相对难度 逮捕蛋白复合物进行结构分析。我的实验室专注于理解的GPCR-arrestin 信号通路。我们已经开发了一种稳定GPCR-arrestin复合物的新型工具 用于冷冻电子显微镜研究，并使用它来可视化非典型趋化因子 受体3以近原子分辨率以各种方式与逮捕。在接下来的五年中， 我们计划将研究扩展到许多重要的GPCR-arrestin对，以了解结构 详细信息，以帮助设计性干预措施。这项研究将为详细的方式开放 解剖抑制蛋白介导的GPCR信号的机理，但也针对基于结构 药物设计。