低温电子显微镜揭示了由他类三胞胎对瑞诺丁受体的连续结合和激活
Steven Molinarolo1, Carmen R Valdivia2, Héctor H Valdivia2
1Department of Biochemistry and Molecular Biology, The Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Nature communications
|November 20, 2025
概括
类药物是广泛使用的胆固醇药物,通过与瑞诺丁受体1 (RyR1) 结合,可以引起肌肉问题. 这项研究揭示了阿托瓦斯塔丁.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 类药物是用于胆固醇管理的主要药物.
- 肌肉相关的副作用和拉布地质溶解是已知的他类药物风险.
- 瑞诺丁受体1 (RyR1) 遗传变异与他类药物不耐受有关.
研究的目的:
- 为了确定他类药物是否直接与RyR1结合.
- 阐明他类药物与RyR1相互作用的结构基础.
- 为了帮助开发具有减少RyR1脱效应的他类药物.
主要方法:
- 电子显微镜 (cryo-EM) 结构的确定.
- 在体外结合测试.
- 对阿托瓦斯塔丁-RyR1复合物的结构分析.
主要成果:
- 化EM结构证实RyR1是阿托瓦斯塔丁的意外非目标.
- 阿托瓦斯塔丁在伪电压感应域裂内以一种不寻常的方式结合.
- 每个RyR1亚单元中的三个阿托瓦斯塔丁分子的顺序结合触发了通道的开放.
结论:
- RyR1是阿托瓦斯塔丁的直接非标,解释了一些与肌肉相关的副作用.
- 独特的结合机制为设计更安全的他类药物提供了洞察力.
- 与HMG-CoA减少酶结合的结构比较可以指导未来的药物修饰.
相关概念视频
Antihypertensive Drugs: Action of Calcium Channel Blockers
1.5K
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,...
1.5K
Antianginal Drugs: Calcium Channel Blockers and Ranolazine
1.3K
Angina pectoris, a primary symptom of ischemic heart disease, requires careful pharmacological interventions. In this context, calcium channel blockers (CCBs) and ranolazine have emerged as crucial pharmacotherapeutic agents, providing deep insights into the complexities of angina management.
CCBs, a diverse class that includes dihydropyridines (nifedipine) and diphenylalkylamines (verapamil and diltiazem), exert their effect by blocking calcium channels in cardiac and smooth muscle cells. This...
CCBs, a diverse class that includes dihydropyridines (nifedipine) and diphenylalkylamines (verapamil and diltiazem), exert their effect by blocking calcium channels in cardiac and smooth muscle cells. This...
1.3K
Relaxation of Skeletal Muscles
5.5K
The period of muscle contraction primarily influences the duration of stimulation at the neuromuscular junction (NMJ), the presence of free calcium ions in the sarcoplasm, and the availability of energy or ATP to support contractions.
When an action potential reaches the axon terminal, it depolarizes the membrane and opens voltage-gated sodium channels. Sodium ions enter the cell, further depolarizing the presynaptic membrane. This depolarization causes voltage-gated calcium channels to open....
When an action potential reaches the axon terminal, it depolarizes the membrane and opens voltage-gated sodium channels. Sodium ions enter the cell, further depolarizing the presynaptic membrane. This depolarization causes voltage-gated calcium channels to open....
5.5K
Ligand-Gated Ion Channel Receptor: Gating Mechanism
3.7K
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...
3.7K
Calmodulin-dependent Signaling
6.0K
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,...
6.0K
Ligand-gated Ion Channels
13.9K
Ligand-gated ion channels are transmembrane proteins with a channel for ions to pass through and a binding site for a ligand. The channel opens only when a ligand attaches to the binding site.
Three Subfamilies of Ligand-gated Ion Channels
Ligand-gated ion channels fall into three subfamilies. The 'Cys-loop' includes the nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA), glycine, and 5-hydroxytryptamine receptors. The second one is the 'Pore-loop' channels that...
Three Subfamilies of Ligand-gated Ion Channels
Ligand-gated ion channels fall into three subfamilies. The 'Cys-loop' includes the nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA), glycine, and 5-hydroxytryptamine receptors. The second one is the 'Pore-loop' channels that...
13.9K


