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Measuring G-protein-coupled Receptor Signaling via Radio-labeled GTP Binding
Published on: June 9, 2017
对G蛋白结合受体细胞外表面的体特异调节
Michael P Bokoch1, Yaozhong Zou, Søren G F Rasmussen
1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature
|January 8, 2010
概括
多种G蛋白结合受体 (GPCRs) 的细胞外表面与体结合部位结合. 针对这些表面提供了一种新的策略,用于开发高度选择性的药物.
科学领域:
- 生物化学和结构生物学.
- 药理学 药理学是指药理学的学科.
- 分子和细胞生物学分子和细胞生物学
背景情况:
- G蛋白结合受体 (GPCR) 是关键的跨膜蛋白和主要的药物标.
- 它们的细胞外表面 (ECS) 多样化,为亚型选择性药物发现提供了潜力.
- 对于ECS在受体激活中的功能作用及其与结合部位的合仍然不清楚.
研究的目的:
- 为了研究GPCR ECS.中的联体特异性构造变化.
- 为了探索ECS和orthosteric连接体结合口袋之间的功能合.
- 评估针对ECS用于全性药物开发的潜力.
主要方法:
- 使用了核磁共振 (NMR) 光谱学.
- 研究了β(2) 上腺素受体ECS的结构动力学.
- 分析了具有不同功效的药物诱导的独特的ECS构造.
主要成果:
- 不同的药物疗效 (激动剂,对抗剂,逆激动剂) 稳定了独特的ECS形状.
- 证实了ECS与orthosteric结合部位之间的直接形状合.
- 揭示了超越静态晶体结构的动态GPCR行为.
结论:
- GPCR ECS与正结合部位的形状联系在一起.
- 针对多样化的ECS可以产生具有高亚型选择性的全调节器.
- 核磁共振研究为GPCR动态和激活机制提供了新的见解.
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G-protein Coupled Receptors
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
G-protein Coupled Receptors
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
Transducer Mechanism: G Protein–Coupled Receptors
G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical, 7TM, or...
GPCRs are also called heptahelical, 7TM, or...
G Protein-coupled Receptors
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
G Protein-coupled Receptors
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
Amplifying Signals via Enzymatic Cascade
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...

