拉莫三嗪
化学
利鲁唑
钠通道
作用机理
药理学
拉考沙胺
对接(动物)
药品
药物发现
结合位点
大麻酚
癫痫
谷氨酸受体
医学
钠
生物化学
受体
神经科学
生物
大麻
护理部
有机化学
体外
精神科
作者
Jian Huang,Xinye Fan,Xin Jin,Liming Teng,Nieng Yan
标识
DOI:10.1073/pnas.2309773120
摘要
Voltage-gated sodium (Nav) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Nav channels serve as the primary targets for several classes of widely used and investigational drugs, including local anesthetics, antiepileptic drugs, antiarrhythmics, and analgesics. In this study, we present cryogenic electron microscopy (cryo-EM) structures of human Nav1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 Å and 2.7 Å, respectively. A 3D EM reconstruction of ligand-free Nav1.7 was also obtained at 2.1 Å resolution. RLZ resides in the central cavity of the pore domain and is coordinated by residues from repeats III and IV. Whereas one LTG molecule also binds to the central cavity, the other is found beneath the intracellular gate, known as site BIG. Therefore, LTG, similar to lacosamide and cannabidiol, blocks Nav channels via a dual-pocket mechanism. These structures, complemented with docking and mutational analyses, also explain the structure-activity relationships of the LTG-related linear 6,6 series that have been developed for improved efficacy and subtype specificity on different Nav channels. Our findings reveal the molecular basis for these drugs' mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs.
科研通智能强力驱动
Strongly Powered by AbleSci AI