Structural Basis and Molecular Mechanism of GPCR-Arrestin Interactions

项目总结/摘要 G蛋白偶联受体本质上是细胞的分子信使， 将信号从外部传递到内部。信号是非常多样化的，包括一个单一的 光子、钙离子、神经递质和激素。人类有800多个GPCR 但只有三种类型的转换器，G蛋白，GPCR激酶 （GRK）和抑制素。GRKs磷酸化GPCR，而G蛋白和抑制蛋白直接 结合GPCR，将信号发送到下游效应器并引起细胞应答。比较 结合G蛋白和抑制蛋白的GPCR结构将为研究GPCR的作用机制提供有价值的见解。 功能选择性和指导设计更有效的药物具有更好的安全性。那里 目前报道了超过300种GPCR−G蛋白复合物的结构，但只有8种发表 GPCR-抑制蛋白复合物的结构，这突出了获得合适的 用于结构分析的抑制蛋白复合物。我的实验室专注于研究不足的GPCR-抑制蛋白 信号通路我们已经开发出一种新的工具，稳定GPCR-抑制蛋白复合物 用于冷冻电子显微镜研究，并利用它来可视化非典型趋化因子如何 受体3在近原子分辨率下以各种方式与抑制蛋白结合。在接下来的五年里， 我们计划将研究扩展到许多重要的GPCR-抑制蛋白对，以了解其结构 细节，以帮助设计有选择的干预措施。这项研究将开辟一条详细的道路， 对抑制蛋白介导的GPCR信号传导机制的剖析， 药物设计

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.