粘附GPCRs的GAIN域的通用残留物编号
Florian Seufert1, Guillermo Pérez-Hernández2, Gáspár Pándy-Szekeres3,4
1Institute for Medical Physics and Biophysics, Leipzig University, Medical Faculty, Leipzig, Germany.
Nature communications
|January 2, 2025
概括
在粘附G蛋白结合受体 (aGPCRs) 中发现的古老GAIN域的新编号方案,有助于理解其结构和功能. 这一进步有助于研究GAIN领域相关疾病.
科学领域:
- 结构生物学是结构生物学.
- 分子生物学分子生物学
- 基因组学就是基因组学.
背景情况:
- 诱导GPCR自身蛋白质分解 (GAIN) 域是一个保存的蛋白质折叠,对粘附G蛋白结合受体 (aGPCRs) 的激活至关重要.
- 病理突变经常发生在GAIN域中,但低序列保护使物种和受体类型之间的比较分析复杂化.
- 现有的知识转移受到GAIN领域缺乏标准化编号系统的阻碍.
研究的目的:
- 开发GAIN域的通用残留物编号方案,以便进行跨物种和跨受体的比较.
- 在GPCR数据库 (GPCRdb) 中实施该方案,以实现更广泛的可访问性和应用.
- 为了在GAIN领域内确定保存和与疾病相关的位置.
主要方法:
- 超过14000个模拟的GAIN域结构的结构对齐.
- 开发一种通用残留物编号方案 (GAIN-GRN).
- 在GPCRdb中实施该计划,并分析保护和与疾病相关的位置.
主要成果:
- 建立了一个强大的GAIN-GRN方案,基于结构对齐,使标准化残留物编号成为可能.
- 该方案阐明了GAIN域拓在多种物种的多种aGPCR和同类物种中.
- 在人类aGPCR中确定了保护热点和统计上富含癌症的位置,证明了结构信息的可转移性.
结论:
- GAIN-GRN 方案提供了一个强大的工具来比较 GAIN 域结构和功能.
- 这种标准化编号系统扩展到多囊病1/PKD1类蛋白,允许直接比较GAIN域类型.
- 这些发现促进了假设生成和实验设计,以了解GAIN域功能和相关病理.
更多相关视频
相关概念视频
G Protein-coupled Receptors
11.3K
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...
11.3K
Transducer Mechanism: G Protein–Coupled Receptors
1.8K
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,...
GPCRs are also called heptahelical,...
1.8K
G-protein Coupled Receptors
115.6K
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.
115.6K
GPCR Desensitization
5.8K
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...
5.8K
GPCRs Regulate Adenylyl Cylase Activity
5.3K
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...
5.3K
Activation and Inactivation of G Proteins
6.7K
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...
6.7K


