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.

项目概要/摘要 G蛋白偶联受体本质上是细胞的分子信使， 从外部到内部转换信号的信号是多种多样的，包括单一信号。 光子、钙等离子、神经递质和激素 人类有超过 800 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 (GRK) 和抑制蛋白使 GPCR 磷酸化，而 G 蛋白和抑制蛋白则直接磷酸化。 结合 GPCR，将信号发送到下游效应器并引起细胞反应。 与 G 蛋白和视紫红质抑制蛋白结合的 GPCR 结构将为了解 功能选择性并指导设计更有效、更安全的药物。 目前已报道超过 300 个 GPCR−G 蛋白复合物结构，但仅发表了 8 个 GPCR−arrestin 复合物的结构，这凸显了获得合适的 用于结构分析的抑制蛋白复合物 我的实验室专注于正在研究的 GPCR-抑制蛋白。 我们开发了一种稳定 GPCR-arrestin 复合物的新工具。 用于冷冻电子显微镜研究，并用它来可视化非典型趋化因子 在接下来的五年里，受体 3 以各种方式以近原子分辨率结合视紫红质抑制蛋白。 我们计划将研究扩展到许多重要的 GPCR−arrestin 对，以了解结构 有助于设计选择性干预措施的细节 这项研究将为详细的干预措施开辟道路。 剖析视紫红质抑制蛋白介导的 GPCR 信号传导机制，同时也基于结构 药物设计。