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首页> 外文期刊>Trends in pharmacological sciences >Escaping the flatlands: new approaches for studying the dynamic assembly and activation of GPCR signaling complexes.
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Escaping the flatlands: new approaches for studying the dynamic assembly and activation of GPCR signaling complexes.

机译:逃离平地:研究GPCR信号复合物动态组装和激活的新方法。

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摘要

Despite significant recent advances in molecular and structural studies of G protein-coupled receptors (GPCRs), an understanding of transmembrane signal transduction with chemical precision requires new approaches. Simple binary receptor-ligand or receptor-G protein complex models cannot adequately describe the relevant macromolecular signaling machineries. GPCR signalosomes undergo complex dynamic assembly-disassembly reactions to create allosteric signaling conduits whose properties cannot necessarily be predicted from individual elements alone. The combinatorial possibilities inherent in a system with hundreds of potential components suggest that high-content miniaturized experimental platforms and computational approaches will be required. To study allosteric effects involved in signalosome reaction pathways, a bottom-up approach using multicolor single-molecule detection fluorescence experiments in biochemically defined systems and complemented by molecular dynamics models of macromolecular complexes is proposed. In bridging the gap between molecular and systems biology, this synthetic approach suggests a way forward from the flatlands to multi-dimensional data collection.
机译:尽管最近在G蛋白偶联受体(GPCR)的分子和结构研究中取得了重大进展,但对具有化学精度的跨膜信号转导的理解仍需要新的方法。简单的二元受体-配体或受体-G蛋白复合物模型不能充分描述相关的大分子信号传导机制。 GPCR信号小体会经历复杂的动态组装-拆卸反应,以生成变构信号传导管道,其特性不一定能单独从单个元素中预测出来。具有数百个潜在组件的系统固有的组合可能性表明,将需要高容量的小型化实验平台和计算方法。为了研究涉及信号体反应途径的变构效应,提出了一种自下而上的方法,该方法在生物化学定义的系统中使用多色单分子检测荧光实验,并辅以大分子复合物的分子动力学模型。为了弥合分子生物学和系统生物学之间的鸿沟,这种综合方法为从平地到多维数据收集的发展提供了一条途径。

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