细胞外纳米体查使用结构稳定的GPCR变体
Xin Zhang1,2, Kaixuan Gao1,2, Jia Nie3
1State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
概括
研究人员开发了一种通用方法来稳定特定形状的G蛋白合受体 (GPCR). 这种技术通过提供稳定的受体点来选潜在的治疗方法,有助于药物发现.
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 是一个学科.
背景情况:
- G蛋白结合受体 (GPCRs) 是关键的药物标,但它们的动态性质使连接体查复杂化.
- 在药物开发中,获得稳定,纯化的GPCRs在特定的构造,特别是活性状态,是一个重大挑战.
研究的目的:
- 为加强药物查制定稳定GPCRs在所需形状的通用策略.
- 创建用于识别构造特异性连接体的工具,提高药物发现效率和特异性.
主要方法:
- 一种融合蛋白的新设计,以稳定M1肌糖乙胆受体 (M1R) 在其活性构造中.
- 将稳定策略应用于其他GPCR,以证明可通用性.
- 使用酵母显示技术对纳米体库对稳定活性和非活性M1R状态的选.
主要成果:
- 通过使用设计的融合蛋白成功稳定了M1R在其活性构造中.
- 在不同的GPCR中证明了稳定方法的通用性.
- 确定了特定于形状的纳米体,可以识别不同的M1R状态.
结论:
- 开发的通用方法有效地稳定了GPCRs在特定的结构,克服了药物发现中的一个主要障碍.
- 稳定的GPCRs和识别的纳米体作为开发更有选择性的治疗剂的有价值的工具.
- 这种方法显著提高了GPCR向药物发现的效率和特异性.
相关概念视频
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...
GPCR Desensitization
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
GPCRs Regulate Adenylyl Cylase Activity
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 cells.
Two...
Two...
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...


