对B类G蛋白结合受体进行生物仿真查
Christian Devigny1, Francisco Perez-Balderas, Bastiaan Hoogeland
1Max-Planck-Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany.
Journal of the American Chemical Society
|May 4, 2011
概括
研究人员开发了一种新的高通量方法来研究皮质激素释放因子 (CRF) 与其受体的相互作用,这导致了用于应激反应研究的强效探针.
科学领域:
- 生物化学 生物化学
- 药理学 药理学是指药理学的学科.
- 神经科学是一个神经科学.
背景情况:
- 皮质otropin释放因子 (CRF) 通过与皮质otropin释放因子受体1 (CRF) 结合来调节哺乳动物的应激反应.
- CRF ((1) R是一种B类G蛋白结合受体 (GPCR),是情绪障碍的治疗标.
研究的目的:
- 通过化学探测CRF与其受体的跨膜域之间的分子相互作用.
- 开发一种高通量方法来识别有力的CRF受体激动剂.
- 在体内研究CRF受体的行为作用.
主要方法:
- 合成了以乙标记的类图书馆,并将其与使用铜催化双极循环添加的亚酸修饰载体结合.
- 开发了一种基于细胞的测试方法,以测试由产生的联体激活CRF(1) 受体的活性.
- 利用一种高亲和度载体来增强在体内研究中的绑定的功效.
主要成果:
- 定义了完全激活CRF(1) 受体所需的最小序列动机.
- 确定了关键的功能组和用于受体结合的结构-活性关系.
- 开发了一种针对受体激活域的高强度 (EC(50) = 4 nM) 的优化探头.
- 证明通过载体的膜招募可以提高的功效超过四个数量级.
结论:
- 开发的高通量结合方法有效地模仿了天然的GPCR激活.
- 优化的探头是研究CRF(1) 受体激活在其本地环境中的宝贵工具.
- 这种方法通过消除净化步骤,显著增加了选吞吐量.
- 这些发现提供了对应激反应和情绪障碍潜在治疗策略的见解.
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相关概念视频
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...
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 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.
