Johnston Christopher A, Siderovski David P
Department of Pharmacology, University of North Carolina at Chapel Hill, CB# 7365, Chapel Hill, NC 27599-7365, USA.
Mol Pharmacol. 2007 Aug;72(2):219-30. doi: 10.1124/mol.107.034348. Epub 2007 Apr 12.
G-protein-coupled receptors (GPCRs) serve as catalytic activators of heterotrimeric G-proteins (Galphabetagamma) by exchanging GTP for the bound GDP on the Galpha subunit. This guanine nucleotide exchange factor activity of GPCRs is the initial step in the G-protein cycle and determines the onset of various intracellular signaling pathways that govern critical physiological responses to extracellular cues. Although the structural basis for many steps in the G-protein nucleotide cycle have been made clear over the past decade, the precise mechanism for receptor-mediated G-protein activation remains incompletely defined. Given that these receptors have historically represented a set of rich drug targets, a more complete understanding of their mechanism of action should provide further avenues for drug discovery. Several models have been proposed to explain the communication between activated GPCRs and Galphabetagamma leading to the structural changes required for guanine nucleotide exchange. This review is focused on the structural biology of G-protein signal transduction with an emphasis on the current hypotheses regarding Galphabetagamma activation. We highlight several recent results shedding new light on the structural changes in Galpha that may underlie GDP release.
G蛋白偶联受体（GPCRs）通过将GTP与Gα亚基上结合的GDP进行交换，充当异源三聚体G蛋白（Gαβγ）的催化激活剂。GPCRs的这种鸟嘌呤核苷酸交换因子活性是G蛋白循环的起始步骤，并决定了各种细胞内信号通路的开启，这些信号通路控制着对细胞外信号的关键生理反应。尽管在过去十年中，G蛋白核苷酸循环中许多步骤的结构基础已经明确，但受体介导的G蛋白激活的确切机制仍未完全阐明。鉴于这些受体历来是丰富的药物靶点，更全面地了解其作用机制应为药物发现提供更多途径。已经提出了几种模型来解释活化的GPCRs与Gαβγ之间的通讯，这种通讯导致鸟嘌呤核苷酸交换所需的结构变化。本综述聚焦于G蛋白信号转导的结构生物学，重点关注当前关于Gαβγ激活的假说。我们强调了几个最近的结果，这些结果为可能是GDP释放基础的Gα结构变化提供了新的线索。
