对A族和B族GPCR激活的结构差异的洞察
在PubMed上查看摘要
概括
此摘要是机器生成的。由于TM6的独特结构断裂,B家族的G蛋白结合受体 (GPCRs) 与葡萄糖受体一样,比A家族的受体更慢地激活信号. 这会影响碳水化合物代谢的调节.
科学领域
- 生物化学
- 结构生物学
- 药理学
背景情况
- 乙族G蛋白结合受体 (GPCR) 是碳水化合物代谢的关键调节剂.
- 不同的结构特征,包括跨膜段6 (TM6) α-螺旋突破,使B家族与A家族的GPCR区分开来.
- 了解这些结构差异是阐明受体激活机制的关键.
研究的目的
- 将B家族葡萄糖受体 (GCGR) 与A家族β2上腺受体 (β2AR) 的结构和功能进行比较.
- 研究B家族GPCR中TM6结构破坏的功能后果.
- 阐明不同G蛋白激活率背后的分子机制.
主要方法
- 低温电子显微镜 (cryo-EM) 用于在3.1安格斯特罗姆分辨率下确定GCGR-Gs蛋白质复合物的结构.
- 生物化学测定测量关三酸盐 (GTP) 循环,关二酸盐 (GDP) 释放,GTP结合和G蛋白解离.
- 光和双电子共振 (DEER) 光谱以探测形状变化.
主要成果
- 冷-EM结构显示了GCGR-Gs复合体的TM6螺旋中明显的断裂,与B家族GPCR相一致.
- 与β2AR相比,GCGR的G蛋白激活率显著降低,包括GTP的循环,GDP的释放和G蛋白解离.
- 与β2AR不同的是,单独的激素结合不足以在TM6细胞质末端诱导可检测的外向运动.
结论
- 由GCGR所示的B家族GPCR的TM6中的结构断裂有助于G蛋白激活动力学减缓.
- 这种较慢的激活机制可能代表B家族GPCRs在调节碳水化合物代谢等生理过程中的独特信号范式.
- 对这些差异的进一步研究可以为代谢障碍的向治疗开发提供信息.
相关概念视频
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...
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,...
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...
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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.
The G-protein or guanine nucleotide-binding protein, is a large heterotrimeric complex. Its three subunits...
Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒ small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins,...

