纳米体作为人类感应受体的负调节器
Qianqian Cui1, Lu Wang2, Haonan Wang2
1NEST Lab, Department of Chemistry, College of Science, Shanghai University, Shanghai, 200444, China; The CAS Key Laboratory of Receptor Research, Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Biochemical and biophysical research communications
|December 28, 2023
概括
开发了驼衍生的纳米体,针对感应受体 (CaSR). NB32纳米体通过稳定其非活性状态来抑制CaSR活性,为障碍治疗提供了潜在的可能性.
科学领域:
- 生物化学 生化学
- 药理学 药理学是指药理学的学科.
- 结构生物学 结构生物学
背景情况:
- 人类感应受体 (CaSR) 调节的平衡.
- CaSR突变导致不平衡障碍,如高血症和低血症.
- 而CaSR是治疗这些疾病的重要药物标.
研究的目的:
- 为了产生和识别具有抑制功能的CaSR特定的纳米体.
- 为了描述纳米体的抑制机制,NB32.
- 阐明NB32-CaSR相互作用的结构基础.
主要方法:
- 产生和选127只驼衍生的纳米体对CaSR.
- 功能性测试以评估细胞内调动的抑制.
- 下游信号通路的分析 (G12/13,ERK1/2).
- 对CaSR-NB32复合物的联合结晶和结构确定.
主要成果:
- 从127个候选体中确定了4个抑制纳米体.
- NB32有效地抑制了CaSR介导的细胞内调动.
- NB32抑制了G12/13和ERK1/2信号传递,并增强了calcilytic的有效性.
- 结构分析显示NB32与CaSR LB2域结合,防止原体相互作用并稳定不活跃的受体.
结论:
- NB32是一种强大的CaSR抑制剂,可以稳定受体的非活性构造.
- NB32的机制涉及通过结合LB2域的全调制.
- 这种纳米体代表了与相关疾病的有希望的治疗候选者.
相关概念视频
01:16Calmodulin-dependent Signaling
5.1K
Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
5.1K
01:18Antihypertensive Drugs: Action of Calcium Channel Blockers
526
Calcium ions are essential to contract smooth muscle cells in blood vessels. They enter these cells through voltage-dependent calcium channels, specifically L-type calcium channels in the cell membrane. These L-type calcium channels are integral to the excitation-contraction coupling process in smooth muscle. When a stimulus is received by smooth muscle cells, their membrane depolarizes. This alteration in membrane potential instigates the opening of L-type calcium channels. As a result,...
526
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
2.3K
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
2.3K
01:27Feedback Regulation of Calcium Concentration
3.4K
Calcium is an essential signaling molecule required for various cellular functions. Calcium pumps and ion channels on cell and organellar membranes, such as those on the endoplasmic reticulum (ER), regulate calcium concentrations inside the cell. They remain closed, keeping the cytosolic calcium levels low at a resting state.
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
3.4K
01:27Transducer Mechanism: Enzyme-Linked Receptors
2.5K
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Major types that are helpful drug targets include:
2.5K