The nicotinic acetylcholine receptor has served, since its biochemical identification in the 1970s, as a model of an allosteric ligand-gated ion channel mediating signal transition at the synapse. In recent years, the application of X-ray crystallography and high-resolution cryo–electron microscopy, together with molecular dynamic simulations of nicotinic receptors and homologs, have opened a new era in the understanding of channel gating by the neurotransmitter. They reveal, at atomic resolution, the diversity and flexibility of the multiple ligand-binding sites, including recently discovered allosteric modulatory sites distinct from the neurotransmitter orthosteric site, and the conformational dynamics of the activation process as a molecular switch linking these multiple sites. The model emerging from these studies paves the way for a new pharmacology based, first, upon the occurrence of an original mode of indirect allosteric modulation, distinct from a steric competition for a single and rigid binding site, and second, the design of drugs that specifically interact with privileged conformations of the receptor such as agonists, antagonists, and desensitizers. Research on nicotinic receptors is still at the forefront of understanding the mode of action of drugs on the nervous system.Expected final online publication date for the Annual Review of Biochemistry , Volume 93 is June 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

中文翻译：

---

烟碱乙酰胆碱受体及其五聚体同系物：原子水平信号转导的变构机制

烟碱乙酰胆碱受体自 20 世纪 70 年代被生化鉴定以来，一直作为介导突触信号转换的变构配体门控离子通道的模型。近年来，X射线晶体学和高分辨率冷冻电子显微镜的应用，以及烟碱受体和同系物的分子动力学模拟，开启了神经递质通道门控理解的新时代。他们以原子分辨率揭示了多个配体结合位点的多样性和灵活性，包括最近发现的不同于神经递质正位位点的变构调节位点，以及作为连接这些多个位点的分子开关的激活过程的构象动力学。这些研究中出现的模型为新的药理学铺平了道路，其基础是，首先，间接变构调节的原始模式的出现，与单一刚性结合位点的空间竞争不同，其次，药物的设计与受体的特殊构象（例如激动剂、拮抗剂和脱敏剂）特异性相互作用。烟碱受体的研究仍然处于了解药物对神经系统作用方式的前沿。《生物化学年度评论》第 93 卷的预计最终在线出版日期为 2024 年 6 月。请参阅 http://www.annualreviews。 org/page/journal/pubdates 了解修订后的估计。