脂质G蛋白结合受体的晶体结构
Michael A Hanson1, Christopher B Roth, Euijung Jo
1Receptos, 10835 Road to the Cure, San Diego, CA 92121, USA. mhanson@receptos.com
概括
斯芬戈-1-酸盐受体1 (S1P(1) 的晶体结构揭示了对抗剂如何结合. 干进入受体的受体.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 斯芬辛-1-酸盐 (S1P) 是一种生物活性脂质介质.
- S1P受体调节关键的生理过程,包括免疫细胞贩运和血管发育.
- 了解S1P受体激活是治疗开发的关键.
研究的目的:
- 确定与对抗剂结合的斯芬戈-1-酸盐受体1 (S1P(1) 的晶体结构.
- 阐明连接体进入S1P(1) 结合口袋的机制.
- 为S1P的分子识别和激活提供见解.
主要方法:
- 对S1P(1) 融合到T4-lyszyme (S1P(1) -T4L) 的X射线结晶学与脂模仿对手进行复合.
- 位点定向的突变发生.
- 使用激动剂的结构-活性关系 (SAR) 研究.
- 分子建模. 分子建模.
主要成果:
- 晶体结构揭示了一个封闭的细胞外结合口袋入口.
- 连接物进入结合部位发生在跨膜螺旋体I和VII之间.
- 该结构阐明了分子识别和S1P(1) 激活中对疏水体积的要求.
结论:
- 确定的结构提供了一个详细的分子视图S1P(1) 对抗剂结合.
- 这提供了一个机械的理解,如何连接体访问和激活S1P.
- 这些发现将有助于合理设计S1P受体调节器,用于免疫和肌肉细胞反应.
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 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.
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...
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...


