人类葡萄糖B类G蛋白结合受体的结构
Fai Yiu Siu1, Min He, Chris de Graaf
1Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature
|July 19, 2013
概括
确定了葡萄糖受体 (GCGR) 结构,揭示了结合葡萄糖的独特特征. 这为葡萄糖恒温调节和潜在的治疗点提供了洞察力.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 分子内分泌学分子内分泌学
背景情况:
- 葡萄糖受体 (GCGR) 通过调解葡萄糖对肝脏葡萄糖释放的作用,对葡萄糖稳定至关重要.
- 了解GCGR的分子机制对于管理糖尿病等代谢障碍至关重要.
研究的目的:
- 阐明葡萄糖与人类GCGR结合的结构基础.
- 了解GCGR由其本源连接体葡萄糖的分子识别和激活机制.
主要方法:
- 人类GCGR7跨膜螺旋域的晶体结构确定,分辨率为3.4 Å.
- 广泛的特定位点突变发生以探测受体-连接体相互作用.
- 开发一种与GCGR结合的葡萄糖混合模型.GR.
主要成果:
- 晶体结构揭示了GCGR跨膜域的独特特征,与典型的A类GPCR不同.
- 第一个跨膜螺旋的突出"茎"区域延伸在膜上方,定位细胞外域.
- 葡萄糖结位由细胞外域和茎形成,促进的捕获和与膜外域的相互作用.
结论:
- 确定的结构和结合模型为GCGR如何识别和结合葡萄糖素提供了前所未有的见解.
- GCGR独特的结构元素是其在葡萄糖平衡中发挥作用的关键.
- 这些结构信息可以指导开发针对 GCGR 的新疗法,以治疗代谢疾病.
相关概念视频
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...
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.
Activation and Inactivation of G Proteins
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...


