Affiliation:
1. Department of Molecular Biology, Princeton University, Princeton, NJ 08544
2. Beijing Frontier Research Center for Biological Structures, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
3. Shenzhen Medical Academy of Research and Translation, Shenzhen, Guangdong Province 518107, China
Abstract
Voltage-gated sodium (Nav) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Navchannels 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 Navchannels 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 Navchannels. Our findings reveal the molecular basis for these drugs’ mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs.
Funder
Human Frontier Science Program
Publisher
Proceedings of the National Academy of Sciences
Cited by
2 articles.
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