Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave., N.E., Grand Rapids, MI 49503, USA.
Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave., N.E., Grand Rapids, MI 49503, USA.
Curr Opin Struct Biol. 2017 Aug;45:150-159. doi: 10.1016/j.sbi.2017.05.004. Epub 2017 May 27.
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and are important drug targets for many human diseases. The determination of the 3-D structure of GPCRs and their signaling complexes has promoted our understanding of GPCR biology and provided templates for structure-based drug discovery. In this review, we focus on the recent structure work on GPCR signaling complexes, the β2-adrenoreceptor-Gs and the rhodopsin-arrestin complexes in particular, and highlight the structural features of GPCR complexes involved in G protein- and arrestin-mediated signal transduction. The crystal structures reveal distinct structural mechanisms by which GPCRs recruit a G protein and an arrestin. A comparison of the two complex structures provides insight into the molecular mechanism of functionally selective GPCR signaling, and a structural basis for the discovery of G protein- and arrestin-biased treatments of human diseases related to GPCR signal transduction.
G 蛋白偶联受体（GPCRs）是细胞表面受体中最大的家族，也是许多人类疾病的重要药物靶点。GPCR 及其信号复合物的三维结构的确定促进了我们对 GPCR 生物学的理解，并为基于结构的药物发现提供了模板。在这篇综述中，我们重点介绍了 GPCR 信号复合物的最新结构研究，特别是β2-肾上腺素能受体-Gs 和视紫红质-阻滞蛋白复合物，并强调了参与 G 蛋白和阻滞蛋白介导的信号转导的 GPCR 复合物的结构特征。晶体结构揭示了 GPCR 募集 G 蛋白和阻滞蛋白的不同结构机制。对这两种复合物结构的比较提供了对功能选择性 GPCR 信号转导分子机制的深入了解，也为发现与 GPCR 信号转导相关的人类疾病的 G 蛋白和阻滞蛋白偏向性治疗提供了结构基础。
