{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:30:22Z","timestamp":1781105422752,"version":"3.54.1"},"reference-count":45,"publisher":"National Academy of Sciences","issue":"41","license":[{"start":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T00:00:00Z","timestamp":1696204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000854","name":"Human Frontier Science Program","doi-asserted-by":"publisher","award":["LT000754\/2020-L"],"award-info":[{"award-number":["LT000754\/2020-L"]}],"id":[{"id":"10.13039\/501100000854","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,10,10]]},"abstract":"<jats:p>\n                    Voltage-gated sodium (Na\n                    <jats:sub>v<\/jats:sub>\n                    ) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Na\n                    <jats:sub>v<\/jats:sub>\n                    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 Na\n                    <jats:sub>v<\/jats:sub>\n                    1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 \u00c5 and 2.7 \u00c5, respectively. A 3D EM reconstruction of ligand-free Na\n                    <jats:sub>v<\/jats:sub>\n                    1.7 was also obtained at 2.1 \u00c5 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 Na\n                    <jats:sub>v<\/jats:sub>\n                    channels via a dual-pocket mechanism. These structures, complemented with docking and mutational analyses, also explain the structure\u2013activity relationships of the LTG-related linear 6,6 series that have been developed for improved efficacy and subtype specificity on different Na\n                    <jats:sub>v<\/jats:sub>\n                    channels. Our findings reveal the molecular basis for these drugs\u2019 mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2309773120","type":"journal-article","created":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T15:09:50Z","timestamp":1696259390000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":32,"title":["Dual-pocket inhibition of Na\n                    <sub>v<\/sub>\n                    channels by the antiepileptic drug lamotrigine"],"prefix":"10.1073","volume":"120","author":[{"given":"Jian","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Molecular Biology, Princeton University, Princeton, NJ 08544"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9855-1641","authenticated-orcid":false,"given":"Xiao","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Princeton University, Princeton, NJ 08544"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqin","family":"Jin","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liming","family":"Teng","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4829-7416","authenticated-orcid":false,"given":"Nieng","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Princeton University, Princeton, NJ 08544"},{"name":"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"},{"name":"Shenzhen Medical Academy of Research and Translation, Shenzhen, Guangdong Province 518107, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,10,2]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.57.4.4"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm501981g"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1988"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010818-021757"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau2486"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw2493"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm160"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2695-04.2004"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22485"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","unstructured":"Y. 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