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Open-state structure of veratridine-activated human Nav1.7 reveals the molecular choreography of fast inactivation

Xiao Fan , Jiaofeng Chen , Lingfeng Xue , Huan Wang , Tong Wu , Xiaoshuang Huang , Fangzhou Lu , Xueqin Jin , Chen Song , Jian Huang , Nieng Yan

Vita ››

Vita > Article > DOI: 10.15302/vita.2026.01.0003
Vita Published: Article(id=1220387545134846830, tenantId=1045748351789510663, journalId=1169329684812255232, issueId=0, articleNumber=null, orderNo=null, doi=10.15302/vita.2026.01.0003, pmid=null, cstr=null, oa=null, hot=1, price=null, onlineType=2, articleFormat=0, articleType=null, articleTypeStr=Article, receivedDate=1764691200000, receivedDateStr=2025-12-03, revisedDate=null, revisedDateStr=null, acceptedDate=1768838400000, acceptedDateStr=2026-01-20, onlineDate=1769346684821, onlineDateStr=2026-01-25, pubDate=null, pubDateStr=null, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=null, onlineIssueDateStr=null, onlineJustAcceptDate=1769346684821, onlineJustAcceptDateStr=2026-01-25, onlineFirstDate=1770950423786, onlineFirstDateStr=2026-02-13, sourceXml=null, magXml=null, createTime=1768892664464, creator=13911381637, updateTime=1772176906608, updator=13041195026, issue=null, startPage=null, endPage=null, ext={EN=ArticleExt(id=1220387545269064559, articleId=1220387545134846830, tenantId=1045748351789510663, journalId=1169329684812255232, language=EN, title=Open-state structure of veratridine-activated human Nav1.7 reveals the molecular choreography of fast inactivation, columnId=null, journalTitle=Vita, columnName=, runingTitle=null, highlight=null, articleAbstract=

Nearly all the reported cryogenic electron microscopy (cryo-EM) structures of eukaryotic voltage-gated sodium (Nav) channels, including those of human Nav1.1–Nav1.8, represent various inactivated states, with the characteristic of a non-conductive pore domain surrounded by voltage-sensing domains in varying activated conformations. To capture an open-state Nav structure, we treated human Nav1.7 with a natural neurotoxin veratridine (VTD). Cryo-EM structures of two complexes of VTD-bound Nav1.7 were obtained at overall resolutions of 2.7 Å and 2.9 Å. One, with VTD inserted in the IFM-binding pocket (site I), resembles other inactivated structures; the other, wherein VTD traverses the central cavity (site C), represents an activated conformation with a constriction diameter of 8.2 Å at the intracellular gate. Structural analysis reveals the molecular basis of the bimodal modulation of Nav channels by VTD. More importantly, comparison of the open and inactivated structures elucidates the precise molecular process of fast inactivation in Nav channels.

, authors=

#These authors contribute equally.

, authorsList=Xiao Fan, Jiaofeng Chen, Lingfeng Xue, Huan Wang, Tong Wu, Xiaoshuang Huang, Fangzhou Lu, Xueqin Jin, Chen Song, Jian Huang, Nieng Yan, authorCompany=null, correspAuthors=Nieng Yan, Jian Huang, Chen Song, Xiao Fan, authorNote=null, correspAuthorsNote=
xfan@smart.org.cn
c.song@pku.edu.cn
huangjian@smart.org.cn
nyan@tsinghua.edu.cn
, copyrightStatement=null, copyrightOwner=The Author(s) 2026. Published by Higher Education Press. 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Institute of Chemical Biology (ICB), Shenzhen Bay Laboratory, Guangming District, Shenzhen, Guangdong, China)])])], keywords=null, refs=[Reference(id=1229017487103439410, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=1, rfOrder=0, authorNames=null, journalName=null, refType=null, unstructuredReference=Hille, B. Ion channels of excitable membranes. 3rd Edition. Sunderland: Sinauer Associates (2001)., articleTitle=null, refAbstract=null), Reference(id=1229017487153771059, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1113/jphysiol.1945.sp004114, pmid=null, pmcid=null, year=1945, volume=null, issue=null, pageStart=176, pageEnd=195, url=null, language=null, rfNumber=2, rfOrder=1, authorNames=Hodgkin, A.L., Huxley, A.F., journalName=J. Physiol., refType=null, unstructuredReference=Hodgkin, A.L. & Huxley, A.F. Resting and action potentials in single nerve fibres. J. Physiol. 104, 176–195 (1945)., articleTitle=Resting and action potentials in single nerve fibres, refAbstract=null), Reference(id=1229017487204102708, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1038/s41580-024-00763-7, pmid=null, pmcid=null, year=2024, volume=null, issue=null, pageStart=904, pageEnd=925, url=null, language=null, rfNumber=3, rfOrder=2, authorNames=Huang, J., Pan, X.J., Yan, N., journalName=Nat. Rev. Mol. Cell Biol., refType=null, unstructuredReference=Huang, J., Pan, X.J. & Yan, N. Structural biology and molecular pharmacology of voltage-gated ion channels. Nat. Rev. Mol. Cell Biol. 25, 904–925 (2024)., articleTitle=Structural biology and molecular pharmacology of voltage-gated ion channels, refAbstract=null), Reference(id=1229017487250240053, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1038/nature12822, pmid=null, pmcid=null, year=2013, volume=null, issue=null, pageStart=107, pageEnd=112, url=null, language=null, rfNumber=4, rfOrder=3, authorNames=Liao, M.F., Cao, E.H., Julius, D., Cheng, Y.F., journalName=Nature, refType=null, unstructuredReference=Liao, M.F., Cao, E.H., Julius, D. & Cheng, Y.F. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature 504, 107–112 (2013)., articleTitle=Structure of the TRPV1 ion channel determined by electron cryo-microscopy, refAbstract=null), Reference(id=1229017487300571702, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1126/science.1251652, pmid=null, pmcid=null, year=2014, volume=null, issue=null, pageStart=1443, pageEnd=1444, url=null, language=null, rfNumber=5, rfOrder=4, authorNames=Kühlbrandt, W., journalName=Science, refType=null, unstructuredReference=Kühlbrandt, W. The resolution revolution. Science 343, 1443–1444 (2014)., articleTitle=The resolution revolution, refAbstract=null), Reference(id=1229017487350903351, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1126/science.aal4326, pmid=null, pmcid=null, year=2017, volume=null, issue=null, pageStart=eaal4326, pageEnd=null, url=null, language=null, rfNumber=6, rfOrder=5, authorNames=Shen, H.Z., journalName=Science, refType=null, unstructuredReference=Shen, H.Z. et al. Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution. Science 355, eaal4326 (2017)., articleTitle=Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution, refAbstract=null), Reference(id=1229017487397040696, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1016/j.cell.2017.06.039, pmid=null, pmcid=null, year=2017, volume=null, issue=null, pageStart=470, pageEnd=482.e11, url=null, language=null, rfNumber=7, rfOrder=6, authorNames=Yan, Z., journalName=Cell, refType=null, unstructuredReference=Yan, Z. et al. Structure of the Nav1.4-β1 complex from electric eel. Cell 170, 470–482.e11 (2017)., articleTitle=Structure of the Nav1.4-β1 complex from electric eel, refAbstract=null), Reference(id=1229017487447372345, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1126/science.aau2486, pmid=null, pmcid=null, year=2018, volume=null, issue=null, pageStart=eaau2486, pageEnd=null, url=null, language=null, rfNumber=8, rfOrder=7, authorNames=Pan, X.J., journalName=Science, refType=null, unstructuredReference=Pan, X.J. et al. Structure of the human voltage-gated sodium channel Nav1.4 in complex with β1. Science 362, eaau2486 (2018)., articleTitle=Structure of the human voltage-gated sodium channel Nav1.4 in complex with β1, refAbstract=null), Reference(id=1229017487497703994, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1038/s41467-020-20078-3, pmid=null, pmcid=null, year=2021, volume=null, issue=null, pageStart=128, pageEnd=null, url=null, language=null, rfNumber=9, rfOrder=8, authorNames=Jiang, D.H., journalName=Nat. Commun., refType=null, unstructuredReference=Jiang, D.H. et al. Structural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin. Nat. Commun. 12, 128 (2021)., articleTitle=Structural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin, refAbstract=null), Reference(id=1229017487543841339, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1126/science.aav8573, pmid=null, pmcid=null, year=2019, volume=null, issue=null, pageStart=eaav8573, pageEnd=null, url=null, language=null, rfNumber=10, rfOrder=9, authorNames=Clairfeuille, T., journalName=Science, refType=null, unstructuredReference=Clairfeuille, T. et al. Structural basis of α-scorpion toxin action on Nav channels. Science 363, eaav8573 (2019)., articleTitle=Structural basis of α-scorpion toxin action on Nav channels, refAbstract=null), Reference(id=1229017487589978684, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1016/j.cell.2021.08.021, pmid=null, pmcid=null, year=2021, volume=null, issue=null, pageStart=5151, pageEnd=5162.e11, url=null, language=null, rfNumber=11, rfOrder=10, authorNames=Jiang, D.H., journalName=Cell, refType=null, unstructuredReference=Jiang, D.H. et al. Open-state structure and pore gating mechanism of the cardiac sodium channel. Cell 184, 5151–5162.e11 (2021)., articleTitle=Open-state structure and pore gating mechanism of the cardiac sodium channel, refAbstract=null), Reference(id=1229017487640310333, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1073/pnas.2209164119, pmid=null, pmcid=null, year=2022, volume=null, issue=null, pageStart=e2209164119, pageEnd=null, url=null, language=null, rfNumber=12, rfOrder=11, authorNames=Huang, G.X.Y., journalName=Proc. Natl. Acad. Sci. USA, refType=null, unstructuredReference=Huang, G.X.Y. et al. Unwinding and spiral sliding of S4 and domain rotation of VSD during the electromechanical coupling in Nav1.7. Proc. Natl. Acad. Sci. USA 119, e2209164119 (2022)., articleTitle=Unwinding and spiral sliding of S4 and domain rotation of VSD during the electromechanical coupling in Nav1.7, refAbstract=null), Reference(id=1229017487686447678, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1073/pnas.2322899121, pmid=null, pmcid=null, year=2024, volume=null, issue=null, pageStart=e2322899121, pageEnd=null, url=null, language=null, rfNumber=13, rfOrder=12, authorNames=Li, Z.Q., journalName=Proc. Natl. Acad. Sci. USA, refType=null, unstructuredReference=Li, Z.Q. et al. Dissection of the structure-function relationship of Nav channels. Proc. Natl. Acad. Sci. USA 121, e2322899121 (2024)., articleTitle=Dissection of the structure-function relationship of Nav channels, refAbstract=null), Reference(id=1229017487732585023, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1038/nature05413, pmid=null, pmcid=null, year=2006, volume=null, issue=null, pageStart=894, pageEnd=898, url=null, language=null, rfNumber=14, rfOrder=13, authorNames=Cox, J.J., journalName=Nature, refType=null, unstructuredReference=Cox, J.J. et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 444, 894–898 (2006)., articleTitle=An SCN9A channelopathy causes congenital inability to experience pain, refAbstract=null), Reference(id=1229017487778722368, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1523/JNEUROSCI.2695-04.2004, pmid=null, pmcid=null, year=2004, volume=null, issue=null, pageStart=8232, pageEnd=8236, url=null, language=null, rfNumber=15, rfOrder=14, authorNames=Cummins, T.R., Dib-Hajj, S.D., Waxman, S.G., journalName=J. Neurosci., refType=null, unstructuredReference=Cummins, T.R., Dib-Hajj, S.D. & Waxman, S.G. Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy. J. Neurosci. 24, 8232–8236 (2004)., articleTitle=Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy, refAbstract=null), Reference(id=1229017487824859713, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1073/pnas.0404915101, pmid=null, pmcid=null, year=2004, volume=null, issue=null, pageStart=12706, pageEnd=12711, url=null, language=null, rfNumber=16, rfOrder=15, authorNames=Nassar, M.A., journalName=Proc. Natl. Acad. Sci. USA, refType=null, unstructuredReference=Nassar, M.A. et al. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc. Natl. Acad. Sci. USA 101, 12706–12711 (2004)., articleTitle=Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain, refAbstract=null), Reference(id=1229017487870997058, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1136/jmg.2003.012153, pmid=null, pmcid=null, year=2004, volume=null, issue=null, pageStart=171, pageEnd=174, url=null, language=null, rfNumber=17, rfOrder=16, authorNames=Yang, Y., journalName=J. Med. Genet., refType=null, unstructuredReference=Yang, Y. et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J. Med. Genet. 41, 171–174 (2004)., articleTitle=Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia, refAbstract=null), Reference(id=1229017487933911619, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1126/science.aaw2493, pmid=null, pmcid=null, year=2019, volume=null, issue=null, pageStart=1303, pageEnd=1308, url=null, language=null, rfNumber=18, rfOrder=17, authorNames=Shen, H.Z., Liu, D.L., Wu, K., Lei, J.L., Yan, N., journalName=Science, refType=null, unstructuredReference=Shen, H.Z., Liu, D.L., Wu, K., Lei, J.L. & Yan, N. Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins. Science 363, 1303–1308 (2019)., articleTitle=Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins, refAbstract=null), Reference(id=1229017487984243268, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1016/j.celrep.2022.110735, pmid=null, pmcid=null, year=2022, volume=null, issue=null, pageStart=110735, pageEnd=null, url=null, language=null, rfNumber=19, rfOrder=18, authorNames=Huang, G.X.Y., journalName=Cell Rep., refType=null, unstructuredReference=Huang, G.X.Y. et al. High-resolution structures of human Nav1.7 reveal gating modulation through α-π helical transition of S6IV. Cell Rep. 39, 110735 (2022)., articleTitle=High-resolution structures of human Nav1.7 reveal gating modulation through α-π helical transition of S6IV, refAbstract=null), Reference(id=1229017488030380613, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1038/s41594-022-00860-1, pmid=null, pmcid=null, year=2022, volume=null, issue=null, pageStart=208, pageEnd=1216, url=null, language=null, rfNumber=20, rfOrder=19, authorNames=Zhang, J.T., journalName=Nat. Struct. Mol. Biol., refType=null, unstructuredReference=Zhang, J.T. et al. Structural basis for Nav1.7 inhibition by pore blockers. Nat. Struct. Mol. Biol. 291, 208–1216 (2022)., articleTitle=Structural basis for Nav1.7 inhibition by pore blockers, refAbstract=null), Reference(id=1229017488080712262, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1038/s41467-023-38942-3, pmid=null, pmcid=null, year=2023, volume=null, issue=null, pageStart=3224, pageEnd=null, url=null, language=null, rfNumber=21, rfOrder=20, authorNames=Wu, Q.R., journalName=Nat. Commun., refType=null, unstructuredReference=Wu, Q.R. et al. Structural mapping of Nav1.7 antagonists. Nat. Commun. 14, 3224 (2023)., articleTitle=Structural mapping of Nav1.7 antagonists, refAbstract=null), Reference(id=1229017488126849607, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1038/s41467-023-39307-6, pmid=null, pmcid=null, year=2023, volume=null, issue=null, pageStart=3613, pageEnd=null, url=null, language=null, rfNumber=22, rfOrder=21, authorNames=Huang, J., journalName=Nat. Commun., refType=null, unstructuredReference=Huang, J. et al. Cannabidiol inhibits Nav channels through two distinct binding sites. Nat. Commun. 14, 3613 (2023)., articleTitle=Cannabidiol inhibits Nav channels through two distinct binding sites, refAbstract=null), Reference(id=1229017488172986952, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1073/pnas.2309773120, pmid=null, pmcid=null, year=2023, volume=null, issue=null, pageStart=e2309773120, pageEnd=null, url=null, language=null, rfNumber=23, rfOrder=22, authorNames=Huang, J., Fan, X., Jin, X.Q., Teng, L.M., Yan, N., journalName=Proc. Natl. Acad. Sci. USA, refType=null, unstructuredReference=Huang, J., Fan, X., Jin, X.Q., Teng, L.M. & Yan, N. Dual-pocket inhibition of Nav channels by the antiepileptic drug lamotrigine. Proc. Natl. Acad. Sci. USA 120, e2309773120 (2023)., articleTitle=Dual-pocket inhibition of Nav channels by the antiepileptic drug lamotrigine, refAbstract=null), Reference(id=1229017488219124297, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1085/jgp.87.1.1, pmid=null, pmcid=null, year=1986, volume=null, issue=null, pageStart=1, pageEnd=24, url=null, language=null, rfNumber=24, rfOrder=23, authorNames=Sutro, J.B., journalName=J. Gen. Physiol., refType=null, unstructuredReference=Sutro, J.B. Kinetics of veratridine action on Na channels of skeletal muscle. J. Gen. Physiol. 87, 1–24 (1986)., articleTitle=Kinetics of veratridine action on Na channels of skeletal muscle, refAbstract=null), Reference(id=1229017488265261642, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1085/jgp.87.1.25, pmid=null, pmcid=null, year=1986, volume=null, issue=null, pageStart=25, pageEnd=46, url=null, language=null, rfNumber=25, rfOrder=24, authorNames=Leibowitz, M.D., Sutro, J.B., Hille, B., journalName=J. Gen. Physiol., refType=null, unstructuredReference=Leibowitz, M.D., Sutro, J.B. & Hille, B. Voltage-dependent gating of veratridine-modified Na channels. J. Gen. Physiol. 87, 25–46 (1986)., articleTitle=Voltage-dependent gating of veratridine-modified Na channels, refAbstract=null), Reference(id=1229017488315593291, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1007/BFb0111446, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=18, pageEnd=71, url=null, language=null, rfNumber=26, rfOrder=25, authorNames=null, journalName=null, refType=null, unstructuredReference=Ulbricht, W. The effect of veratridine on excitable membranes of nerve and muscle. In: Brown, L. et al. eds. Reviews of physiology, biochemistry and pharmacology 61. Berlin, Heidelberg: Springer, 18–71 (1969)., articleTitle=null, refAbstract=null), Reference(id=1229017488361730636, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1016/s0026-895x(25)09965-1, pmid=null, pmcid=null, year=1990, volume=null, issue=null, pageStart=144, pageEnd=148, url=null, language=null, rfNumber=27, rfOrder=26, authorNames=Wang, G., Dugas, M., Armah, B.I., Honerjäger, P., journalName=Mol. Pharmacol., refType=null, unstructuredReference=Wang, G., Dugas, M., Armah, B.I. & Honerjäger, P. Sodium channel comodification with full activator reveals veratridine reaction dynamics. Mol. Pharmacol. 37, 144–148 (1990)., articleTitle=Sodium channel comodification with full activator reveals veratridine reaction dynamics, refAbstract=null), Reference(id=1229017488407867981, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1085/jgp.91.3.421, pmid=null, pmcid=null, year=1988, volume=null, issue=null, pageStart=421, pageEnd=443, url=null, language=null, rfNumber=28, rfOrder=27, authorNames=Barnes, S., Hille, B., journalName=J. Gen. Physiol., refType=null, unstructuredReference=Barnes, S. & Hille, B. Veratridine modifies open sodium channels. J. Gen. Physiol. 91, 421–443 (1988)., articleTitle=Veratridine modifies open sodium channels, refAbstract=null), Reference(id=1229017488454005326, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1038/s41401-018-0065-z, pmid=null, pmcid=null, year=2018, volume=null, issue=null, pageStart=1716, pageEnd=1724, url=null, language=null, rfNumber=29, rfOrder=28, authorNames=Zhang, X.Y., Bi, R.Y., Zhang, P., Gan, Y.H., journalName=Acta Pharmacol. Sin., refType=null, unstructuredReference=Zhang, X.Y., Bi, R.Y., Zhang, P. & Gan, Y.H. Veratridine modifies the gating of human voltage-gated sodium channel Nav1.7. Acta Pharmacol. Sin. 39, 1716–1724 (2018)., articleTitle=Veratridine modifies the gating of human voltage-gated sodium channel Nav1.7, refAbstract=null), Reference(id=1229017488500142671, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=30, rfOrder=29, authorNames=null, journalName=null, refType=null, unstructuredReference=DeLano, W.L. The PyMOL molecular graphics system. https://cir.nii.ac.jp/crid/1571980075906330880 (2002)., articleTitle=null, refAbstract=null), Reference(id=1229017488546280016, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1038/s41422-025-01141-4, pmid=null, pmcid=null, year=2025, volume=null, issue=null, pageStart=610, pageEnd=613, url=null, language=null, rfNumber=31, rfOrder=30, authorNames=Fan, X., journalName=Cell Res., refType=null, unstructuredReference=Fan, X. et al. Phrixotoxin-3 binds to three distinct antagonistic sites on human Nav1.6. Cell Res. 35, 610–613 (2025)., articleTitle=Phrixotoxin-3 binds to three distinct antagonistic sites on human Nav1.6, refAbstract=null), Reference(id=1229017488592417361, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1016/j.cell.2023.10.007, pmid=null, pmcid=null, year=2023, volume=null, issue=null, pageStart=5363, pageEnd=5374.e16, url=null, language=null, rfNumber=32, rfOrder=31, authorNames=Gao, S., journalName=Cell, refType=null, unstructuredReference=Gao, S. et al. Structural basis for human Cav1.2 inhibition by multiple drugs and the neurotoxin calciseptine. Cell 186, 5363–5374.e16 (2023)., articleTitle=Structural basis for human Cav1.2 inhibition by multiple drugs and the neurotoxin calciseptine, refAbstract=null), Reference(id=1229017488642749010, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1016/j.chembiol.2024.07.008, pmid=null, pmcid=null, year=2024, volume=null, issue=null, pageStart=1394, pageEnd=1404, url=null, language=null, rfNumber=33, rfOrder=32, authorNames=Jin, X.Q., Huang, J., Wang, H., Wang, K., Yan, N., journalName=Cell Chem. Biol., refType=null, unstructuredReference=Jin, X.Q., Huang, J., Wang, H., Wang, K. & Yan, N. A versatile residue numbering scheme for Nav and Cav channels. Cell Chem. Biol. 31, 1394–1404 (2024)., articleTitle=A versatile residue numbering scheme for Nav and Cav channels, refAbstract=null), Reference(id=1229017488688886355, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1126/science.2425432, pmid=null, pmcid=null, year=1986, volume=null, issue=null, pageStart=361, pageEnd=364, url=null, language=null, rfNumber=34, rfOrder=33, authorNames=Weiss, R.E., Horn, R., journalName=Science, refType=null, unstructuredReference=Weiss, R.E. & Horn, R. Functional differences between two classes of sodium channels in developing rat skeletal muscle. Science 233, 361–364 (1986)., articleTitle=Functional differences between two classes of sodium channels in developing rat skeletal muscle, refAbstract=null), Reference(id=1229017488735023700, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1038/s41467-023-40514-4, pmid=null, pmcid=null, year=2023, volume=null, issue=null, pageStart=5072, pageEnd=null, url=null, language=null, rfNumber=35, rfOrder=34, authorNames=Liu, Y.C., Bassetto, C.A.Z. Jr., Pinto, B.I., Bezanilla, F., journalName=Nat. Commun., refType=null, unstructuredReference=Liu, Y.C., Bassetto, C.A.Z. Jr., Pinto, B.I. & Bezanilla, F. A mechanistic reinterpretation of fast inactivation in voltage-gated Na+ channels. Nat. Commun. 14, 5072 (2023)., articleTitle=A mechanistic reinterpretation of fast inactivation in voltage-gated Na+ channels, refAbstract=null), Reference(id=1229017488781161045, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1126/science.aau2596, pmid=null, pmcid=null, year=2018, volume=null, issue=null, pageStart=eaau2596, pageEnd=null, url=null, language=null, rfNumber=36, rfOrder=35, authorNames=Shen, H.Z., journalName=Science, refType=null, unstructuredReference=Shen, H.Z. et al. Structural basis for the modulation of voltage-gated sodium channels by animal toxins. Science 362, eaau2596 (2018)., articleTitle=Structural basis for the modulation of voltage-gated sodium channels by animal toxins, refAbstract=null), Reference(id=1229017488827298390, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=https://www.nature.com/articles/s41467-025-65587-1, pmid=null, pmcid=null, year=2025, volume=null, issue=null, pageStart=10565, pageEnd=null, url=null, language=null, rfNumber=37, rfOrder=36, authorNames=Liu, Y., journalName=Nat. Commun., refType=null, unstructuredReference=Liu, Y. et al. Molecular basis of sodium channel inactivation. Nat. Commun. 16, 10565 (2025)., articleTitle=Molecular basis of sodium channel inactivation, refAbstract=null), Reference(id=1229017488873435735, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1085/jgp.62.4.375, pmid=null, pmcid=null, year=1973, volume=null, issue=null, pageStart=375, pageEnd=391, url=null, language=null, rfNumber=38, rfOrder=37, authorNames=Armstrong, C.M., Bezanilla, F., Rojas, E., journalName=J. Gen. Physiol., refType=null, unstructuredReference=Armstrong, C.M., Bezanilla, F. & Rojas, E. Destruction of sodium conductance inactivation in squid axons perfused with pronase. J. Gen. Physiol. 62, 375–391 (1973)., articleTitle=Destruction of sodium conductance inactivation in squid axons perfused with pronase, refAbstract=null), Reference(id=1229017488919573080, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1073/pnas.89.22.10910, pmid=null, pmcid=null, year=1992, volume=null, issue=null, pageStart=10910, pageEnd=10914, url=null, language=null, rfNumber=39, rfOrder=38, authorNames=West, J.W., journalName=Proc. Natl. Acad. Sci. USA, refType=null, unstructuredReference=West, J.W. et al. A cluster of hydrophobic amino acid residues required for fast Na+-channel inactivation. Proc. Natl. Acad. Sci. USA 89, 10910–10914 (1992)., articleTitle=A cluster of hydrophobic amino acid residues required for fast Na+-channel inactivation, refAbstract=null), Reference(id=1229017488965710425, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1073/pnas.2100069118, pmid=null, pmcid=null, year=2021, volume=null, issue=null, pageStart=e2100069118, pageEnd=null, url=null, language=null, rfNumber=40, rfOrder=39, authorNames=Li, Z.Q., journalName=Proc. Natl. Acad. Sci. USA, refType=null, unstructuredReference=Li, Z.Q. et al. Structure of human Nav1.5 reveals the fast inactivation-related segments as a mutational hotspot for the long QT syndrome. Proc. Natl. Acad. Sci. USA 118, e2100069118 (2021)., articleTitle=Structure of human Nav1.5 reveals the fast inactivation-related segments as a mutational hotspot for the long QT syndrome, refAbstract=null), Reference(id=1229017489011847770, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1073/pnas.2100066118, pmid=null, pmcid=null, year=2021, volume=null, issue=null, pageStart=e2100066118, pageEnd=null, url=null, language=null, rfNumber=41, rfOrder=40, authorNames=Pan, X.J., journalName=Proc. Natl. Acad. Sci. USA, refType=null, unstructuredReference=Pan, X.J. et al. Comparative structural analysis of human Nav1.1 and Nav1.5 reveals mutational hotspots for sodium channelopathies. Proc. Natl. Acad. Sci. USA 118, e2100066118 (2021)., articleTitle=Comparative structural analysis of human Nav1.1 and Nav1.5 reveals mutational hotspots for sodium channelopathies, refAbstract=null), Reference(id=1229017489057985115, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1080/19336950.2018.1475794, pmid=null, pmcid=null, year=2018, volume=null, issue=null, pageStart=176, pageEnd=186, url=null, language=null, rfNumber=42, rfOrder=41, authorNames=Hu, R.M., journalName=Channels, refType=null, unstructuredReference=Hu, R.M. et al. Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients. Channels 12, 176–186 (2018)., articleTitle=Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients, refAbstract=null), Reference(id=1229017489112511068, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1111/j.1540-8167.2005.40711.x, pmid=null, pmcid=null, year=2005, volume=null, issue=null, pageStart=486, pageEnd=493, url=null, language=null, rfNumber=43, rfOrder=42, authorNames=Itoh, H., Shimizu, M., Takata, S., Mabuchi, H., Imoto, K., journalName=J. Cardiovasc. Electrophysiol., refType=null, unstructuredReference=Itoh, H., Shimizu, M., Takata, S., Mabuchi, H. & Imoto, K. A novel missense mutation in the SCN5A gene associated with Brugada syndrome bidirectionally affecting blocking actions of antiarrhythmic drugs. J. Cardiovasc. Electrophysiol. 16, 486–493 (2005)., articleTitle=A novel missense mutation in the SCN5A gene associated with Brugada syndrome bidirectionally affecting blocking actions of antiarrhythmic drugs, refAbstract=null), Reference(id=1229017489158648413, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1152/ajpheart.00539.2010, pmid=null, pmcid=null, year=2011, volume=null, issue=null, pageStart=H288, pageEnd=H299, url=null, language=null, rfNumber=44, rfOrder=43, authorNames=Huang, H., Priori, S.G., Napolitano, C., O'Leary, M.E., Chahine, M., journalName=Am. J. Physiol. Heart Circ. Physiol., refType=null, unstructuredReference=Huang, H., Priori, S.G., Napolitano, C., O'Leary, M.E. & Chahine, M. Y1767C, a novel SCN5A mutation, induces a persistent Na+ current and potentiates ranolazine inhibition of Nav1.5 channels. Am. J. Physiol. Heart Circ. Physiol. 300, H288–H299 (2011)., articleTitle=Y1767C, a novel SCN5A mutation, induces a persistent Na+ current and potentiates ranolazine inhibition of Nav1.5 channels, refAbstract=null), Reference(id=1229017489208980062, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1161/01.CIR.0000069273.51375.BD, pmid=null, pmcid=null, year=2003, volume=null, issue=null, pageStart=2233, pageEnd=2237, url=null, language=null, rfNumber=45, rfOrder=44, authorNames=Clancy, C.E., Tateyama, M., Liu, H.J., Wehrens, X.H.T., Kass, R.S., journalName=Circulation, refType=null, unstructuredReference=Clancy, C.E., Tateyama, M., Liu, H.J., Wehrens, X.H.T. & Kass, R.S. Non-equilibrium gating in cardiac Na+ channels: an original mechanism of arrhythmia. Circulation 107, 2233–2237 (2003)., articleTitle=Non-equilibrium gating in cardiac Na+ channels: an original mechanism of arrhythmia, refAbstract=null), Reference(id=1229017489255117407, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1186/1471-2105-7-339, pmid=null, pmcid=null, year=2006, volume=null, issue=null, pageStart=339, pageEnd=null, url=null, language=null, rfNumber=46, rfOrder=45, authorNames=Meng, E.C., Pettersen, E.F., Couch, G.S., Huang, C.C., Ferrin, T.E., journalName=BMC Bioinformatics, refType=null, unstructuredReference=Meng, E.C., Pettersen, E.F., Couch, G.S., Huang, C.C. & Ferrin, T.E. Tools for integrated sequence-structure analysis with UCSF Chimera. BMC Bioinformatics 7, 339 (2006)., articleTitle=Tools for integrated sequence-structure analysis with UCSF Chimera, refAbstract=null), Reference(id=1229017489297060448, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1016/s0263-7855(97)00009-x, pmid=null, pmcid=null, year=1996, volume=null, issue=null, pageStart=354, pageEnd=360, url=null, language=null, rfNumber=47, rfOrder=46, authorNames=Smart, O.S., Neduvelil, J.G., Wang, X.N., Wallace, B.A., Sansom, M.S.P., journalName=J. Mol. Graph., refType=null, unstructuredReference=Smart, O.S., Neduvelil, J.G., Wang, X.N., Wallace, B.A. & Sansom, M.S.P. HOLE: a program for the analysis of the pore dimensions of ion channel structural models. J. Mol. Graph. 14, 354–360 (1996)., articleTitle=HOLE: a program for the analysis of the pore dimensions of ion channel structural models, refAbstract=null), Reference(id=1229017489343197793, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1073/pnas.2208211119, pmid=null, pmcid=null, year=2022, volume=null, issue=null, pageStart=e2208211119, pageEnd=null, url=null, language=null, rfNumber=48, rfOrder=47, authorNames=Huang, X.S., journalName=Proc. Natl. Acad. Sci. USA, refType=null, unstructuredReference=Huang, X.S. et al. Structural basis for high-voltage activation and subtype-specific inhibition of human Nav1.8. Proc. Natl. Acad. Sci. USA 119, e2208211119 (2022)., articleTitle=Structural basis for high-voltage activation and subtype-specific inhibition of human Nav1.8, refAbstract=null), Reference(id=1229017489389335138, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1073/pnas.2220578120, pmid=null, pmcid=null, year=2023, volume=null, issue=null, pageStart=e2220578120, pageEnd=null, url=null, language=null, rfNumber=49, rfOrder=48, authorNames=Fan, X., Huang, J., Jin, X.Q., Yan, N., journalName=Proc. Natl. Acad. Sci. USA, refType=null, unstructuredReference=Fan, X., Huang, J., Jin, X.Q. & Yan, N. Cryo-EM structure of human voltage-gated sodium channel Nav1.6. Proc. Natl. Acad. Sci. USA 120, e2220578120 (2023)., articleTitle=Cryo-EM structure of human voltage-gated sodium channel Nav1.6, refAbstract=null), Reference(id=1229017489435472483, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1038/s41592-019-0580-y, pmid=null, pmcid=null, year=2019, volume=null, issue=null, pageStart=1146, pageEnd=1152, url=null, language=null, rfNumber=50, rfOrder=49, authorNames=Tegunov, D., Cramer, P., journalName=Nat. Methods, refType=null, unstructuredReference=Tegunov, D. & Cramer, P. Real-time cryo-electron microscopy data preprocessing with Warp. Nat. Methods 16, 1146–1152 (2019)., articleTitle=Real-time cryo-electron microscopy data preprocessing with Warp, refAbstract=null), Reference(id=1229017489481609828, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1038/nmeth.4169, pmid=null, pmcid=null, year=2017, volume=null, issue=null, pageStart=290, pageEnd=296, url=null, language=null, rfNumber=51, rfOrder=50, authorNames=Punjani, A., Rubinstein, J.L., Fleet, D.J., Brubaker, M.A., journalName=Nat. Methods, refType=null, unstructuredReference=Punjani, A., Rubinstein, J.L., Fleet, D.J. & Brubaker, M.A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017)., articleTitle=cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination, refAbstract=null), Reference(id=1229017489531941477, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1107/S0907444910007493, pmid=null, pmcid=null, year=2010, volume=null, issue=null, pageStart=486, pageEnd=501, url=null, language=null, rfNumber=52, rfOrder=51, authorNames=Emsley, P., Lohkamp, B., Scott, W.G., Cowtan, K., journalName=Acta Crystallogr. D Biol. Crystallogr., refType=null, unstructuredReference=Emsley, P., Lohkamp, B., Scott, W.G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010)., articleTitle=Features and development of Coot, refAbstract=null), Reference(id=1229017489578078822, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1107/S0907444912001308, pmid=null, pmcid=null, year=2012, volume=null, issue=null, pageStart=352, pageEnd=367, url=null, language=null, rfNumber=53, rfOrder=52, authorNames=Afonine, P.V., journalName=Acta Crystallogr. D Biol. Crystallogr., refType=null, unstructuredReference=Afonine, P.V. et al. Towards automated crystallographic structure refinement with phenix.refine. Acta Crystallogr. D Biol. Crystallogr. 68, 352–367 (2012)., articleTitle=Towards automated crystallographic structure refinement with phenix.refine, refAbstract=null), Reference(id=1229017489624216167, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1107/S2059798318002425, pmid=null, pmcid=null, year=2018, volume=null, issue=null, pageStart=519, pageEnd=530, url=null, language=null, rfNumber=54, rfOrder=53, authorNames=Croll, T.I., journalName=Acta Crystallogr. D Struct. Biol., refType=null, unstructuredReference=Croll, T.I. ISOLDE: a physically realistic environment for model building into low-resolution electron-density maps. Acta Crystallogr. D Struct. Biol. 74, 519–530 (2018)., articleTitle=ISOLDE: a physically realistic environment for model building into low-resolution electron-density maps, refAbstract=null), Reference(id=1229017489666159208, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1002/jcc.20945, pmid=null, pmcid=null, year=2008, volume=null, issue=null, pageStart=1859, pageEnd=1865, url=null, language=null, rfNumber=55, rfOrder=54, authorNames=Jo, S., Kim, T., Iyer, V.G., Im, W., journalName=J. Comput. Chem., refType=null, unstructuredReference=Jo, S., Kim, T., Iyer, V.G. & Im, W. CHARMM-GUI: a web-based graphical user interface for CHARMM. J. Comput. Chem. 29, 1859–1865 (2008)., articleTitle=CHARMM-GUI: a web-based graphical user interface for CHARMM, refAbstract=null), Reference(id=1229017489712296553, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1016/j.softx.2015.06.001, pmid=null, pmcid=null, year=2015, volume=null, issue=null, pageStart=19, pageEnd=25, url=null, language=null, rfNumber=56, rfOrder=55, authorNames=Abraham, M.J., journalName=SoftwareX, refType=null, unstructuredReference=Abraham, M.J. et al. GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1–2, 19–25 (2015)., articleTitle=GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers, refAbstract=null), Reference(id=1229017489754239594, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1038/nmeth.4067, pmid=null, pmcid=null, year=2017, volume=null, issue=null, pageStart=71, pageEnd=73, url=null, language=null, rfNumber=57, rfOrder=56, authorNames=Huang, J., journalName=Nat. Methods, refType=null, unstructuredReference=Huang, J. et al. CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat. Methods 14, 71–73 (2017)., articleTitle=CHARMM36m: an improved force field for folded and intrinsically disordered proteins, refAbstract=null), Reference(id=1229017489800376939, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1063/1.2408420, pmid=null, pmcid=null, year=2007, volume=null, issue=null, pageStart=014101, pageEnd=null, url=null, language=null, rfNumber=58, rfOrder=57, authorNames=Bussi, G., Donadio, D., Parrinello, M., journalName=J. Chem. Phys., refType=null, unstructuredReference=Bussi, G., Donadio, D. & Parrinello, M. Canonical sampling through velocity rescaling. J. Chem. Phys. 126, 014101 (2007)., articleTitle=Canonical sampling through velocity rescaling, refAbstract=null), Reference(id=1229017489846514284, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1063/1.328693, pmid=null, pmcid=null, year=1981, volume=null, issue=null, pageStart=7182, pageEnd=7190, url=null, language=null, rfNumber=59, rfOrder=58, authorNames=Parrinello, M., Rahman, A., journalName=J. Appl. Phys., refType=null, unstructuredReference=Parrinello, M. & Rahman, A. Polymorphic transitions in single crystals: a new molecular dynamics method. J. Appl. Phys. 52, 7182–7190 (1981)., articleTitle=Polymorphic transitions in single crystals: a new molecular dynamics method, refAbstract=null), Reference(id=1229017489892651629, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1063/1.464397, pmid=null, pmcid=null, year=1993, volume=null, issue=null, pageStart=10089, pageEnd=10092, url=null, language=null, rfNumber=60, rfOrder=59, authorNames=Darden, T., York, D., Pedersen, L., journalName=J. Chem. Phys., refType=null, unstructuredReference=Darden, T., York, D. & Pedersen, L. Particle mesh Ewald: an N⋅log(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089–10092 (1993)., articleTitle=Particle mesh Ewald: an N⋅log(N) method for Ewald sums in large systems, refAbstract=null), Reference(id=1229017489938788974, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H, pmid=null, pmcid=null, year=1997, volume=null, issue=null, pageStart=1463, pageEnd=1472, url=null, language=null, rfNumber=61, rfOrder=60, authorNames=Hess, B., Bekker, H., Berendsen, H.J.C., Fraaije, J.G.E.M., journalName=J. Comput. Chem., refType=null, unstructuredReference=Hess, B., Bekker, H., Berendsen, H.J.C. & Fraaije, J.G.E.M. LINCS: a linear constraint solver for molecular simulations. J. Comput. Chem. 18, 1463–1472 (1997)., articleTitle=LINCS: a linear constraint solver for molecular simulations, refAbstract=null), Reference(id=1229017489989120623, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, doi=10.1002/jcc.21787, pmid=null, pmcid=null, year=2011, volume=null, issue=null, pageStart=2319, pageEnd=2327, url=null, language=null, rfNumber=62, rfOrder=61, authorNames=Michaud-Agrawal, N., Denning, E.J., Woolf, T.B., Beckstein, O., journalName=J. Comput. Chem., refType=null, unstructuredReference=Michaud-Agrawal, N., Denning, E.J., Woolf, T.B. & Beckstein, O. MDAnalysis: a toolkit for the analysis of molecular dynamics simulations. J. Comput. 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Bimodal regulation of Nav1.7 by VTD may be explained by the dual binding poses on the PD.

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Site I binding contributes to the antagonistic effect of VTD on Nav channels.

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VTD binding at site C opens the pore.

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Structural changes between the open and fast-inactivated Nav1.7.

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The “door wedge” allosteric mechanism governing Nav channel fast inactivation.

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Open-state structure of veratridine-activated human Nav1.7 reveals the molecular choreography of fast inactivation

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ABSTRACT

Nearly all the reported cryogenic electron microscopy (cryo-EM) structures of eukaryotic voltage-gated sodium (Nav) channels, including those of human Nav1.1–Nav1.8, represent various inactivated states, with the characteristic of a non-conductive pore domain surrounded by voltage-sensing domains in varying activated conformations. To capture an open-state Nav structure, we treated human Nav1.7 with a natural neurotoxin veratridine (VTD). Cryo-EM structures of two complexes of VTD-bound Nav1.7 were obtained at overall resolutions of 2.7 Å and 2.9 Å. One, with VTD inserted in the IFM-binding pocket (site I), resembles other inactivated structures; the other, wherein VTD traverses the central cavity (site C), represents an activated conformation with a constriction diameter of 8.2 Å at the intracellular gate. Structural analysis reveals the molecular basis of the bimodal modulation of Nav channels by VTD. More importantly, comparison of the open and inactivated structures elucidates the precise molecular process of fast inactivation in Nav channels.

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INTRODUCTION

In multicellular organisms, electrical signaling is indispensable for nearly all neuronal activities and a wide range of physiological processes1-3. Voltage-gated sodium (Nav) channels govern the initiation and transmission of electrical signals in the form of action potentials in excitable systems such as neurons and muscles. Nav channels activate upon membrane depolarization, followed by fast inactivation that ensures the repetitive and directional firing of action potentials1-3. Following decades of rigorous investigation into their physiological and pathophysiological roles, recent investigations have mainly been focused on elucidating the structure–function relationship of Nav channels. The technological breakthrough in single-particle cryogenic electron microscopy (cryo-EM) has led to the structural determination of human Nav1.1–Nav1.83-8.

Most of the mammalian Nav structures captured to date represent inactivated states, which are featured with a non-conductive pore domain (PD), depolarized or “up” voltage-sensing domains (VSDs), and the fast inactivation motif, Ile/Phe/Met (IFM), wedged in the receptor site adjacent to the intracellular gate3. Towards an in-depth and comprehensive understanding of their working mechanisms, structural snapshots of Nav channels in all major states are indispensable. The structure of Nav channels in the activated or resting state remains to be determined.

Many strategies have been employed to lock the purified Nav channels in distinct conformations. Certain peptide toxins successfully trap VSDIV in a down conformation, but the other three VSDs and PD remain unchanged9,10. One structure of a rat Nav1.5 mutant rNav1.5-QQQ, in which the IFM motif was replaced by Gln/Gln/Gln, was announced to be the open state in the presence of the open-pore blocker propafenone11. However, there is a key mismatch between the structural model and the 3D EM reconstruction. As will be elaborated later, our molecular dynamics simulation (MDS) analysis of the original and corrected structures of rNav1.5-QQQ suggested that neither could be conductive.

To probe Nav gating transitions, we engineered a series of point mutations to modulate the voltage dependence of activation and inactivation of Nav1.7 channels12,13. In the structure of Nav1.7-M11, a mutant that contains eleven rationally designed single point mutations, VSDI displays a completely down conformation and the PD is in a tightly contracted state, lacking the fenestrations seen in other inactivated Nav structures12. Electrophysiological characterizations suggest that the structure of Nav1.7-M11 may represent a closed-state inactivation (CSI) conformation. The structural study of Nav1.7-M11 demonstrates the feasibility of capturing Nav1.7 in distinct functional states. In fact, Nav1.7 has been more extensively characterized structurally than other subtypes, due in part to the well-established genetic evidence linking it to pain sensation and subsequent efforts targeting it for analgesic development14-17. Since 2019, more than twenty human Nav1.7 structures have been determined in complex with diverse modulators3,12,13,18-23. Nav1.7 also yields the highest resolution for any Nav structures, at 2.2 Å for the overall structure19.

Encouraged by these results, we continued to focus on human Nav1.7 with the goal of determining its structures in both resting and activated states. In an attempt to determine the structure of Nav1.7 in the activated state, we treated the channel with veratridine (VTD), an alkaloid neurotoxin derived from the lily family that is known to act as a potent Nav opener24-26. VTD preferentially binds the activated sodium channel, inducing a hyperpolarizing shift. This promotes channel opening at more negative potentials and delays inactivation, leading to more persistent activation at resting membrane potential24-26. On the other hand, VTD binding lowers the peak current; single-channel recordings show reduced conductance27,28.

Here, we report the cryo-EM structures of wild-type (WT) Nav1.7 in two distinct conformations, each with one VTD bound. The structure of Nav1.7 with VTD standing near the IFM motif, defined as site I (I for inactivation), is reminiscent of the cannabidiol (CBD)-bound, inactivated state22. The other structure, where the elongated steroidal alkaloid VTD traverses the spacious cavity of the PD (site C), appears to represent the activated conformation with all four VSDs in the up state and an open pore. This open-state structure reflects a potentially conductive conformation in our MDS analysis. Structural comparison of Nav1.7 in the activated and inactivated states elucidates the dynamic details for fast inactivation, and reveals the pathogenic mechanism for dozens of disease-related mutations.

RESULTS

Distinct structures of Nav1.7 treated with VTD

Prior to the cryo-EM analysis of VTD in complex with human Nav1.7, we validated the functional effects of the purchased VTD. Human Nav1.7 channels, WT or mutants, were transiently expressed in HEK293T cells for whole-cell patch-clamp electrophysiological recordings, treated with VTD under different conditions.

With standard steady-state activation and inactivation protocols (see Materials and Methods), VTD induced a pronounced hyperpolarizing shift in both activation and inactivation curves (Supplementary Fig. S1 and Tables S1–S4). In the meantime, it suppressed the peak current amplitude in a dose-dependent manner, with an IC50 of 92.7 ± 18.4 μM (Fig. 1a). VTD also elicited a persistent inward current and a prominent tail current, both of which were enhanced with increasing concentrations of VTD (Fig. 1a, left). To amplify these small-amplitude currents and probe VTD’s use-dependent modulation, we applied a 5-Hz pulse protocol. Upon repetitive depolarizations, VTD produced cumulative peak current inhibition and enhanced tail current induction, yielding an EC50 for the tail current of 95.4 ± 16.6 μM (Fig. 1a, middle and right). The distinctive bimodal modulation of suppression of peak current and induction of persistent and tail currents is consistent with the reported effects of VTD on Nav channels29.

For structural determination, we co-expressed human Nav1.7 with auxiliary β1 and β2 subunits and conducted protein purification and cryo-sample preparation following an established workflow12,18. Considering the limited solubility, VTD was included throughout the purification process to ensure sufficient channel occupancy. When VTD was applied at 100 μM, three major classes of reconstructions were obtained after cryo-EM data acquisition and processing (Supplementary Figs. S2, S3, and Table S5). One class has no VTD density, representing an apo form that is identical to the reported WT structure19 (Supplementary Fig. S3e). In another class, the density that clearly belongs to a VTD molecule stands next to the IFM motif (Supplementary Figs. S3d, S4). The overall structure remains similar to the apo channel, with a root-mean-square deviation (RMSD) of 0.96 Å over 1,244 Cα atoms in the α subunit when superimposed in PyMOL30 (Fig. 1b). Local shifts occur in the cytosolic tip of S6III as a result of the insertion of the VTD molecule (Fig. 1b, right). Based on our recently proposed definition for ligand binding sites on Nav and Cav channels, this VTD binds to site I 21,31. We refer to this structure as Nav1.7V_I, which features an inactivated state.

The last class displays marked changes in VTD binding and channel conformation. The elongated VTD molecule traverses the entire central cavity (site C), with its 4,9-epoxycevan and 3,4-dimethoxybenzoate ends pointing to fenestrations I–II and III–IV, respectively (Fig. 1c). We will call this structure Nav1.7V_O. As will be demonstrated later, the intracellular gate is sufficiently widened in this conformation to conduct Na+. Unlike CBD, lacosamide, and lamotrigine, each of which simultaneously binds to two sites on the PD21-23, the pore states in class I and class O are different, suggesting exclusive binding of VTD to site I or site C in these two conformations.

Similar binding poses of VTD and CBD at site I

The overall structure of Nav1.7V_I is similar to the CBD-bound one, with an RMSD of 0.92 Å over 1,239 Cα atoms (Fig. 2a; Supplementary Fig. S4a). As aforementioned, two CBD molecules simultaneously bind to the PD of Nav1.7, one penetrating the fenestration (site F) and the other fortifying the IFM binding site by standing next to Ile and Phe22. In Nav1.7V_I, only one VTD is observed in the PD. The 3,4-dimethoxybenzoate moiety inserts into the corner enclosed by S4−5III, S6III, and S6IV, surrounded mostly by hydrophobic residues. The remaining portion of the molecule, containing the cevanine skeleton, projects toward the cytosol (Fig. 2a, b). This binding pose is compatible with its higher aqueous solubility conferred by several hydroxy groups.

Consistent with the similar binding poses at site I, both VTD and CBD reduce the peak currents and stabilize an inactivated state, the latter manifested by the leftward shift of the voltage-dependence for steady-state inactivation (Supplementary Fig. S1)22. As the mechanism of action of modulators associated with site I has been elaborated in our previous work22,31,32, we refrain from repeating these details in the current work, but focus on the other binding pose of VTD.

Gate opening upon VTD binding to site C

In Nav1.7V_O, VTD, along its long axis, is closer to repeats II and III (Fig. 3a, left panel). The molecule is coordinated through extensive hydrophobic and polar interactions. S6III engages four residues, Ser1445, Thr1448, Leu1449, and Phe1452, more than any other individual segments (Fig. 3a; Supplementary Fig. S4b). Leu393 and Ile397 on S6I, Leu960 on S6II, Trp1332 on S5III, and Ile1745 on S6IV contribute to the van der Waals contacts with VTD. The C-terminal residues of the P1 helices in repeat I–III, Thr359, Cys925, and Ala1403, all use their backbone carbonyl oxygen to hydrogen (H)-bonded with the hydroxyl groups of VTD. Phe1405 on the selectivity filter (SF) loop in repeat III also participates in VTD binding (Fig. 3a, right panels).

The PD of Nav1.7V_O is evidently dilated. Calculation of the radii of the permeation path reveals a constriction site diameter of 8.2 Å, sufficient to permeate a 7.2-Å hydrated Na+ ion (Fig. 3b). By comparison, the gate for WT apo channel is 5.0 Å (Fig. 3b). Previously, structural study of rNav1.5-QQQ suggested an open gate (Fig. 3b). However, re-examination of its deposited map (EMD-31519) and structural coordinates (PDB: 7FBS) revealed an error in model building (Supplementary Fig. S5). An incorrectly assigned π-helix at segment SI:400–403 induces a positional shift of all the residues downstream of Gly401, resulting in inaccurate analysis of the permeation path (Supplementary Fig. S5a).

We rebuilt and refined the PD of rNav1.5-QQQ against the deposited map. The updated coordinates (rNav1.5-QQQ-rebuilt) substantially improved model fitting to the density map and enhanced model quality metrics across all validation parameters (Supplementary Fig. S5d). In rNav1.5-QQQ-rebuilt, the segment SI:390–429 shows an RMSD of 3.3 Å over 40 Cα atoms compared to the original model, and the rest of the PD remains nearly identical, with an RMSD of 0.4 Å over 542 Cα atoms. The gate diameter of the rebuilt model is 5.6 Å, slightly smaller than that of the original model, 6.2 Å (Supplementary Fig. S5e). The rebuilt rNav1.5-QQQ model will be used for all major comparisons and analyses unless otherwise stated.

HOLE analysis confirms that, among all publicly available Nav structures, Nav1.7V_O presented in this study is the only one with the gate diameter large enough to potentially allow the permeation of hydrated Na+ ions. We will present the MDS characterization of the open pore in the next section. In the following, we examine the mechanism by which VTD dilates the channel.

The two classes of VTD-bound structures can be superimposed with an RMSD of 1.2 Å over 1,180 aligned Cα pairs. Despite the prominent structural deviations of the PD segments, most of the VTD-coordinating residues remain nearly unchanged at site C, except those on S6III. In particular, Thr1448 and Leu1449 would sterically clash with VTD without a major displacement (Fig. 3c). Of note, Ala substitution of Thr1448 would still need to undergo the conformational changes to avoid the clash between VTD and the Cβ atom. By contrast, replacement of Leu1449 by Ala may avoid the steric clash even when the PD is contracted as in the apo or class I state. Along this line of thinking, Ala substitution of Leu960, a residue on S6II that anchors the other end of VTD, may also provide extra space to accommodate VTD in the absence of a major shift of S6III.

To test this analysis, we generated Nav1.7 mutants with single-point mutations, L960A, T1448A or L1449A. Whereas T1448A had no significant effect on the bimodal regulation of Nav1.7 by VTD, both L960A and L1449A led to a nearly complete loss of both the persistent and tail currents (Fig. 3d; Supplementary Figs. S6, S7). Meanwhile, these two mutations each rendered Nav1.7 more sensitive to VTD inhibition, which was especially evident in the use-dependent measurement (Fig. 3d–g; Supplementary Fig. S6). Therefore, Leu960 and Leu1449 appear to be two key residues that couple the site C binding of VTD to pore opening. Interestingly, according to our recently proposed versatile residue numbering scheme for Nav channels33, these two key residues (Leu960S6II,29; Leu1449S6III,29) are located at the corresponding positions on S6II and S6III, respectively.

Open conformation of the intracellular gate in Nav1.7V_O

In the 3D EM map of Nav1.7V_O, the IFM-containing III–IV linker (residues 1465–1497) is completely invisible. Compared to the IFM-loaded apo Nav1.7 structure, the fenestration on the interface of repeats III and IV is directly connected to the intracellular gate, leaving a wide cleft (Fig. 4a). We performed MDS of PD in Nav1.7V_O, with VTD removed, to examine whether the substantially widened gate is permeable to hydrated Na+ ions. The PDs of WT human Nav1.7 and the original and rebuilt rNav1.5-QQQ were analyzed in parallel.

The simulations of PDs were conducted under a transmembrane potential of 120 mV. The intracellular gate is fully hydrated in the Nav1.7V_O structure (Supplementary Video S1). Consistently, ion permeation analysis confirmed the permeation of Na+ ions with a calculated conductance of 13.8 ± 5.0 pS, which is comparable to the experimental value34 (Fig. 4d; Supplementary Video S1). In contrast, the apo WT hNav1.7 and the two rNav1.5-QQQ structures exhibited minimal hydration at the corresponding region, unable to permeate Na+ ions in our MDS analysis (Fig. 4b, c; Supplementary Video S1).

We also characterized the dynamic process of Na+ permeation through the channel (Fig. 4e). Na+ ions remained hydrated as they passed through the intracellular gate (Supplementary Video S1). Furthermore, trajectory analysis showed an asymmetric path for the Na+ ions, which are preferentially located near S6IV and the wide cleft between S6III and S6IV (Fig. 4f).

Structural basis for fast inactivation

We previously, in the absence of an open structure, suggested that the IFM motif might execute a fast cutoff of the ion flow mainly through pushing S6IV to close the intracellular gate7,8. Determination of an open structure of Nav1.7 fills a critical void in understanding the process of fast inactivation and offers an updated view on the cascade of molecular events that complete the fast inactivation in Nav channels.

When the structures of Nav1.7V_O and the apo channel are overlaid, there is nearly no change in their VSDs, all of which exhibit the depolarized or up conformations (Fig. 5a, left). By contrast, the S5 and S6 segments and the S4–5 constriction ring in all four repeats undergo structural changes to varying degrees (Fig. 5a, right). In all the available Nav structures, including Nav1.7V_O, the SF and its supporting P1, P2, and the upper halves of S5 and S6 segments remain rigid (Fig. 5b). We will hereafter refer to this region as the PD shoulder.

Superimposition of Nav1.7V_O and the apo structures relative to the shoulder shows tilt of the S6 segments in repeats II–IV, all starting around the fourth helical turn. Note that in repeats I–III, a conserved Gly is positioned on this helical turn, likely representing the key residue that provides the flexibility for the downstream segment (Fig. 5b). At first sight, the cytosolic half of S6III undergoes the most marked displacement, with the Cα atom of the cytosolic tip moving by 8.0 Å; those of S6IV and S6II are displaced by 4.5 Å and 4.3 Å, respectively; S6I seems to be nearly unchanged (Fig. 5a, right). Scrutiny of the structure shows that the fourth helical turn in S6I undergoes an α→π relaxation from the open to the inactivated state, an important structural shift that reorganizes the inner wall of the pore cavity (Fig. 5b).

Then what are the determinants that lead to the structural re-arrangement of the pore-forming segments? When the IFM motif is accessing the receptor site, the Phe residue, which would clash with Asn1753 and Ile1756 on S6IV, directly pushes Ile1756 toward the S6I segment (Fig. 5c, upper inset). Meanwhile, the dragging force exerted by the shift of the III–IV helix, a process that has been analyzed by us and others previously7,10,35, and the van der Waals attractions of Phe1460 on S6III to the Ile and Phe residues in IFM together pull the cytoplasmic terminus of S6III toward S6IV.

The displacements of S6III and S6IV have a profound effect on the pore conformation. Concerted pushing of S6IV and pulling of S6III collectively narrows the intracellular gate, making it impermeable to Na+ ions (Fig. 5a, right). The side cleft between S6III and S6IV in the open pore is now stitched by an array of hydrophobic residues, only leaving a small fenestration on the interface of repeats III and IV (Fig. 5d, left). On the other side of S6IV, the displacement of residues Val1758 and Ile1759 would clash with Ile394 and Leu398 on S6I, respectively, if there were no additional conformational changes. The α→π helical transition in the middle turn of S6I affords the solution. The rotation of the ensuing S6I segment turns the bulky hydrophobic chains of Ile394 and Leu398 away, repositioning Ala399 to interact with Ile1759. Another consequence of the α→π shift is to re-orient Phe391 to interact with Tyr1755, further shrinking the volume of the central cavity (Fig. 5d, right). The concomitant events accompanying the formation of the IFM binding site and plugging of IFM to this site quickly stop ion flow at the narrowed gate.

The above analysis shows that both S6III and S6IV only undergo swing motions, without axial rotation, to close the gate. However, the “apo” channel, like in most other Nav structures, has a glyco-diosgenin (GDN)-like density penetrating its intracellular gate. We previously analyzed in detail that this conformation, despite having a non-conductive gate, appears to be less ideal for IFM accommodation due to the placement of a polar residue Asn1753 adjacent to the hydrophobic Phe residue from IFM19 (Fig. 5c, insets). We have also observed that the S6IV segment tends to adopt the π form in the presence of channel antagonists, such as Protoxin II (ProTx-II), Huwentoxin IV, and a number of small-molecule inhibitors19,21-23. We have shown that the simple α→π transition of the single segment S6IV would have multiple consequences, including reshaping the IFM-binding site to a more agreeable hydrophobic cavity, further tightening the intracellular gate to an extent that is too narrow for GDN binding, and closing or narrowing the III–IV and IV–I fenestrations19.

When the PD structures of Nav1.7V_O and the ProTx-II-bound Nav1.7 are superimposed relative to the shoulder, the α→π rotation in the middle of S6IV is evident (Fig. 5e, left). Consequently, while the Phe in IFM pushes Asn1753 and Ile1756 away, it also attracts Met1754 to revolve toward the hydrophobic cluster formed by Phe1460, Ile and Phe in the IFM motif (Figs. 5e, right and 6a; Supplementary Video S2).

DISCUSSION

The structural analyses presented here reveal the molecular foundation for the dual actions of VTD on Nav channels. Binding to site I stabilizes an inactivated state, consistent with the left shift of the steady-state inactivation curve when the channels are treated with VTD (Supplementary Fig. S1). Inhibition of the peak currents is likely a collective result of VTD binding to both sites, and site C binding appears to be responsible for the use-dependence of peak current reduction as well as the induced persistent currents (Fig. 1a).

The binding pose of VTD at site C is consistent with the reported observation in single-channel recording that VTD led to both reduced conductance and increased open probability27,28. Channel opening may be induced when VTD is accessing site C. Then, what is the entry site? Is VTD initially docked to site I and subsequently travels to site C, or does it approach the cavity from the fenestrations or the intracellular gate? Addressing this question requires comprehensive characterizations. The static structures reported here set the framework for future computational and experimental analyses.

Uniform or diverse PD conformations in fast inactivation?

Prior to the determination of an open Nav structure in this study, the PD has mainly displayed three non-conductive conformations among the dozens of eukaryotic Nav structures: tight, relaxed, and loose. The PD in NavPaS and Nav1.7-M11 represent the most contracted conformation, wherein the diameter of the intracellular gate is less than 2 Å6,12,36. This sealed gate cannot accommodate any lipid. In a relaxed PD, exemplified by the “π-form” of the ProTx-II- and HWTX-IV-bound Nav1.7, the constriction site is less than 3 Å in diameter, still disallowing the penetration of a steroid-like molecule19. In the majority of the Nav structures, the intracellular gate, with a diameter between 5–6 Å, is penetrated with a GDN-like molecule, and we refer to this state as the loose PD (Fig. 6b). Note that three similar states of the PD have been observed in Cav channels, although the detailed parameters, such as the gate diameter and the α or π form of the S6 segments, vary32.

Nav1.7-M11, with its tight PD and one down VSD, may represent the CSI conformation. Does the tight PD resemble that in the resting channels? To answer this question, a bona fide resting-state structure is necessitated. By contrast, all four VSDs are up in the Nav structures with relaxed or loose PD3. Then, which represents the fast inactivated conformation, the relaxed, the loose, or both? We previously suggested that the relaxed state, in which the chemical environment is more compatible with IFM insertion, may reflect the fast inactivated state. Yet, a key question concerns the steroid-like molecule in the intracellular gate in the loose conformation. If the density is only from a GDN or a cholesterol hemisuccinate, which was supplemented in high concentration during channel purification, such a conformation is, in essence, an artifact. However, is it possible that a cholesterol or steroid molecule may insert into the gate even under physiological conditions? If so, how quickly can it occur? Is it related to slow inactivation? It is noted that a recent study suggested that fast inactivation might involve rotation of the S6III and S6IV segments37. Although no rotation of S6III is observed when the structures of the open and relaxed channels are compared, the S6IV segment does undergo an α→π transition in addition to the swing motion of the helix. This observation further supports that the relaxed conformation may correspond to the fast inactivated state.

Disease mutations mapped to the inactivation segments

Because fast inactivation in Nav channels is critical to numerous physiological processes, its mechanism has been studied for decades. Two primary models, the ball-and-chain model38 and the hinged-lid model38,39, have been proposed to explain the experimental data. Based on the structural comparison of NavPaS and EeNav1.4, we proposed the “door wedge” model, in which docking of the IFM motif into its receptor site allosterically drives pore closure6,7. The study presented here, which reports the long-sought-after structure of an open conformation for the eukaryotic Nav channels, provides direct evidence to support the wedge model (Fig. 6c).

In addition, we previously analyzed dozens of disease-associated mutations that are clustered into two mechanistic classes within the context of the wedge model40,41. Mutations that weaken IFM-receptor interactions directly compromise the fast inactivation, and those that hinder the conformational coupling required for III–IV linker displacement and pore closure influence the process indirectly (Fig. 6d). Both perturbations would favor channel opening during prolonged depolarization, resulting in a left shift in steady-state inactivation, enhanced persistent or tail currents, and accelerated recovery from inactivation.

Determination of the open-state structure of Nav1.7, particularly with the identification of additional coupling residues, has advanced our mechanistic understanding of many Nav disease mutations. We will use the generic numbering33 to describe some of the disease mutations as they have been identified in multiple Nav subtypes. One cluster of mutations resides in the III–IV fenestration, including PheS6III,40, MetS6IV,31, IleS6IV,33, and AlaS6IV,34, and the other lies in the IV–I fenestration, including AsnS6I,30, LeuS6I,33, TyrS6IV,32, and IleS6IV,33 (Fig. 6d). Y1781C/HS6IV,32, I1782M/SS6IV,33, and A1783T/VS6IV,34 have been found in patients with Nav1.1-related DRVT, N406K/SS6I,30, L409VS6I,33, F1473CS6III,40, M1766LS6IV,31, Y1767CS6IV,32, and I1768VS6IV,33 in Nav1.5-associated long QT syndrome 3 (LQT3), L407FS6I,33 in Nav1.6-linked developmental and epileptic encephalopathy 13 (DEE13), and N395KS6I,30 and F1460VS6III,40 in Nav1.7-related primary erythermalgia. LQT3 mutations such as Y1767CS6IV,32 and N406KS6I,30 promote elevated late INa, and all these mutations accelerate recovery from inactivation compared with WT channels, suggesting destabilization of the inactivated state42-45.

In sum, the structures of VTD-bound Nav1.7 reveal the molecular basis for the dual modulations of Nav1.7 by the long-studied small molecule neurotoxin. The open-conformation of VTD-potentiated Nav1.7 fills an important void in the structural biology of Nav channels and establishes the framework for a detailed understanding of channel gating and fast inactivation.

MATERIALS AND METHODS

Whole cell electrophysiology

We applied a protocol similar to our previous publication with minor adjustments40,48-49. All currents were recorded in HEK293T cells. Cells were transiently co-transfected with human Nav1.7 and eGFP using Lipofectamine 2000 (Invitrogen). Cells with green fluorescence were randomly selected for patch-clamp recordings 24–48 h after transfection. All experiments were performed at room temperature.

Currents were recorded using an EPC10-USB amplifier with Patchmaster software v2*90.2 (HEKA Elektronik), filtered at 3 kHz (low-pass Bessel filter) and sampled at 50 kHz. The borosilicate pipettes (Sutter Instrument) used in all experiments had a resistance of 2–4 MΩ, series resistance was compensated by > 75%. The electrodes were filled with the internal solution composed of 105 mM CsF, 40 mM CsCl, 10 mM NaCl, 10 mM EGTA, and 10 mM HEPES, pH adjusted to 7.4 with CsOH. The external solution contained 140 mM NaCl, 4 mM KCl, 1.5 mM CaCl2, 1 mM MgCl2, 10 mM ᴅ-glucose, and 10 mM HEPES, pH adjusted to 7.4 with NaOH. The linear component of leaky currents and capacitive transients were subtracted using the P/4 procedure. Only cells with high seal resistance (> 1 GΩ) were used.

To investigate VTD’s effects on Nav1.7, veratridine was dissolved in dimethyl sulfoxide (DMSO, Sigma) to make a stock solution of 100 mM and stored at –20 °C. Working solutions were freshly prepared and perfused to the recording cell using a multichannel perfusion system (VM8, ALA) for several minutes until the pharmacological effect reached saturation. Prior to drug application, cells were recorded for 5–15 min to establish a stable peak current.

To assess the inhibitory effect of VTD on the peak current, cells were held at –120 mV and depolarized to a test pulse to 0 mV for 50 ms. To investigate the use-dependent effect, a train of 30 pulses (5-ms duration to 0 mV) was applied at 5 Hz from a holding potential of –120 mV. The accumulated tail current at the end of the stimulation was normalized to the amplitude of the first peak current. Concentration–response curves were fitted with: Y = Bottom + (Top – Bottom) / (1 + 10^((LogIC50–X) * Hill Slope)), where IC50 or EC50 represents the drug concentration that inhibits 50% of the peak current or activates 50% of the tail current, respectively; X is log of the drug concentration; and Hill Slope is the slope factor.

To characterize channel gating properties, voltage-dependent activation was assessed using a protocol consisting of steps from a holding potential of –120 mV to voltages ranging from –90 mV to +80 mV for 50 ms in 5-mV increments. Conductance (G) was calculated as G = I / (V – Vr), where Vr is the reversal potential. Normalized conductance was plotted against the test voltage (from –90 mV to +30 or +40 mV) to generate activation curves. Voltage-dependent steady-state inactivation was determined with a two-pulse protocol, in which cells were conditioned with 1,000-ms pre-pulses from –130 mV (or –150 mV for Nav1.7-L1449A) to 0 mV in 5-mV increments, followed by a 50-ms test pulse to 0 mV. Normalized peak currents were plotted against pre-pulse voltage to construct inactivation curves. Both activation and inactivation relationships were fitted with a Boltzmann function to determine the V1/2 and slope factors (k).

To ensure data integrity, rigorous quality control criteria were applied, excluding activation curves with (k) ≤4. Data were processed using Fitmaster (HEKA Elektronik), Igor Pro (WaveMetrics), and GraphPad Prism (GraphPad Software). All quantitative data are presented as mean ± SEM, with n representing the number of independently recorded cells. Statistical significance was assessed using one-way ANOVA and the extra sum-of-squares F test.

Cell culture and transient expression of human Nav1.7 complex in HEK293F cells

The proteins were expressed using the same codon-optimized constructs from our previous work, specifically human Nav1.7 (Uniprot Q15858), β1 subunit (Uniprot Q07699), and β2 subunit (Uniprot O60939) in pCAG expression vector. HEK293F cells (Thermo Fisher Scientific, R79007) were maintained in SMM 293T-II medium (Sino Biological Inc.) at 37 °C under 5% CO2 and 60% humidity. For transient expression of the human Nav1.7 complex, each liter of culture at a density of 1.5–2.0 × 106 cells per mL was transfected with a mixture of 2.5 mg plasmids, including 1.5 mg Nav1.7, 0.5 mg β1, and 0.5 mg β2. The plasmid mixture was pre-incubated with 4 mg 40-kDa linear PEI (Polysciences) in 50 mL fresh medium for 15–30 min.

Protein purification of human Nav1.7-VTD complexes

Transfected HEK293F cells (24 L) were harvested ~48 h post-transfection by centrifugation at 3,600× g for 10 min and resuspended in lysis buffer containing 25 mM Tris-HCl (pH 7.5) and 150 mM NaCl. The suspension was supplemented with 0.1 μM VTD (MCE), 2 mM PMSF, and protease inhibitor cocktail (Selleckchem), followed by incubation at 4 °C with gentle rotation for 30 min. n-Dodecyl-β-ᴅ-maltopyranoside (DDM, Anatrace) was then added to a final concentration of 1% (w/v), along with cholesteryl hemisuccinate Tris salt (CHS, Anatrace) at 0.1% (w/v). The mixture was incubated at 4 °C for an additional 2 h. The supernatant obtained by centrifugation at 16,000× g for 45 min was applied to anti-FLAG M2 affinity resin (Sigma) and incubated for batch binding. The resin was washed four times with wash buffer (buffer W) containing 25 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.06% GDN, 0.1 μM VTD, and protease inhibitors. Bound proteins were eluted with buffer W supplemented with 0.2 mg/mL FLAG peptide (GenScript). The eluent was subsequently passed through Strep-Tactin Sepharose resin (IBA) by gravity flow, washed four times with buffer W, and eluted with buffer W containing 2.5 mM desthiobiotin. The final eluate was concentrated using a 100-kDa molecular weight cut-off Amicon filter unit (Millipore) and subjected to size-exclusion chromatography on a Superose 6 10/300 GL column (GE Healthcare) pre-equilibrated in buffer containing 25 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.02% GDN, and 0.1 mM veratridine. The peak fractions were pooled supplemented with 0.5 mM veratridine and incubated at 4 °C for 30 min; then concentrated to ~10 mg/mL for cryo-grid preparation.

Cryo-EM sample preparation and data acquisition

UltrAuFoil (R1.2/1.3 300 mesh, Quantifoil) grids were glow-discharged with easiGlow (PELCO) using 15 mA for 15 s at 0.37 mBar. Vitrobot Mark IV chamber was pre-cooled to 10 °C with 100% humidity. 3 μL concentrated Nav1.7-VTD was applied to a freshly treated grid, which was then blotted with filter paper for 4 s and plunged into liquid ethane cooled by liquid nitrogen. Grids were loaded to a 300 kV Titan Krios G3i with spherical aberration (Cs) image corrector (Thermo Fisher Scientific). Micrographs were automated recorded in SerialEM by a GIF Quantum K2 Summit camera (Gatan) with a 20 eV slit in super-resolution mode at a nominal magnification of 105,000×, resulting in a calibrated pixel size of 0.557 Å. Each movie stack was exposed for 5.6 s (0.175 s per frame, 32 frames) with a total electron dose of ~50 e2. The movie stacks were aligned, summed and dose-weighted using Warp50 and binned to a pixel size of 1.114 Å per pixel.

Data processing

A total of 5,021 micrographs were collected and preprocessed on-the-fly in Warp50, then imported into cryoSPARC51. Particles from 100 micrographs were initially auto-picked using blob picking and subjected to 2D classification to generate templates. Class averages displaying clear features were selected for template-based particle picking for the full dataset and Ab-initio reconstruction. Picked and extracted bin4 particles were further cleaned via 2D classification to remove obvious junk. The cleaned dataset was subjected to heterogeneous refinement using two initial references derived from Ab-initio reconstruction. Bin2 particles were re-extracted from selected good class, followed by four rounds of heterogeneous refinement and duplicate removal. The best-resolved class was extracted into bin1 for further processing. The selected particles were subjected to two additional rounds of heterogeneous refinement incorporating higher-resolution features. Subsequent non-uniform refinement of the dominant class, comprising 631,118 particles, yielded a reconstruction at an overall resolution of 2.7 Å. In this reconstruction, the S6III segment exhibited branched density, suggesting a mixed conformational state. To resolve structural heterogeneity, unsupervised 3D classification was performed on the 631,118 particles without providing multiple manually defined references. A range of different initial resolution filters and class numbers, with “force hard classification” enabled, was tried. Classification with a 6 Å low-pass filter and four output classes successfully resolved three distinct conformational states: the open state, the site I-bound state, and the apo state. The resulting 3D classes were subsequently used as references for heterogeneous refinement, followed by a final round of non-uniform refinement. Final reconstructions were obtained at overall resolutions of 2.9 Å for the open state (133,758 particles, 21.2%), 2.7 Å for the site I-bound state (335,177 particles, 53.1%), and 2.9 Å for the apo state (162,183 particles, 25.7%).

Model building and refinement

The published apo-state structure (PDB: 7w9k) was applied as the initial model for hNav1.7–VTD complexes and underwent manual inspection and adjustments in COOT52. The VTD molecules were then modeled and refined based on the density in COOT52. Subsequent refinement was performed using the real-space refinement in PHENIX53, followed by molecular dynamics-based optimization in ISOLDE54. A final round of real-space refinement in PHENIX53 was conducted to complete and validate the model. Validation results are detailed in Supplementary Table S5.

MDS

The protein models were built with our cryo-EM structures of hNav1.7V_O, hNav1.7 apo, and the previously resolved structure rNav1.5-QQQ (PDB: 7FBS), as well as its rebuilt version. Only the PDs (residue 233–409, 850–977, 1306–1463, and 1629–1769 in Nav1.7, and residue 236–429, 824–945, 1320–1481, and 1644–1777 in Nav1.5) were included in the simulation systems. CHARMM-GUI55 was used to build the simulation systems. The protein models were embedded into a POPC lipid bilayer. After membrane insertion, the system was solvated in 0.15 M NaCl solution. The simulation box was around 10 × 10 × 12 nm3, which comprised ~120,000 atoms.

We performed MDS with GROMACS56 version 2021.2, using the CHARMM36m force field57 and CHARMM TIP3P water model. For all the production simulations, the time step was 2 fs. The v-rescale algorithm with a time constant of 0.5 ps was used to maintain the temperature at 310 K58, and the Parrinello-Rahman algorithm with a time constant of 5 ps was used to maintain the pressure at 1 bar59. The Particle-Mesh Ewald method was used to calculate long-range electrostatics with a cut-off of 1.2 nm60, and the van der Waals interactions were smoothly switched off from 1.0 nm to 1.2 nm. The bonds involving hydrogen were constrained using the LINCS algorithm61. The MDAnalysis package62 was used to analyze the MDS results. PyMOL was used to render molecular visualizations30. The default CHARMM-GUI protocol was used to progressively equilibrate the system, including 5,000 steps of energy minimization, 250 ps NVT equilibration, and 1,625 ps NPT equilibration. Then we restrained the Cα atoms of the protein with a force constant of 1,000 kJ/mol/nm2 to perform another 100 ns NPT equilibration. For production simulations, we relaxed the restraints of the pore helix (10 residues before and after the DEKA locus in the SF), while the Cα atoms in other regions were still restrained. We performed ion permeation simulations by applying an electric field of 0.01 V/nm along the pore axis pointing to the intracellular direction, which generated a transmembrane potential of ~120 mV. Three replicates of 1.5 μs simulations were performed for each simulation system.

Water distribution analysis

The water distribution around the intracellular gate was estimated from production simulation trajectories. The origin was assigned as the mean position of the four Cα atoms of DEKA locus, and then the pore axis was assigned as the z-axis. By binning the z-axis into 2 Å grid and calculating the number of water molecules around 1 nm of the pore axis, we obtained the water density distribution along the z-axis from the following equation:

ρ=NV=Nπr2Δz

where ρ is water density, N is the number of water molecules observed in the cylinder layer, V is the volume of the cylinder layer, r(= 1 nm) is the radius of the cylinder, Δz(= 2 Å) is the grid-spacing. Then the density distribution was normalized by the water density in bulk solution.

Ion permeation analysis

The permeation events were determined by analyzing the z coordinates of ion trajectories: if an ion moved from the extracellular side across the membrane to the intracellular side, one permeation event was counted. By counting the number of permeation events, the conductance of the channel for ion (gion) can be calculated as follows:

gion=IV=NpQiontV=NpQiontELz

where Np is the observed number of permeation events, Qion is the charge of the permeating ion, t is the simulation time, V is the transmembrane potential, E is the applied electric field, and Lz is the box size in the z direction. Errors were estimated by the standard deviations of three replicates.

Distribution analysis of permeating ions at the gate

To evaluate the asymmetry of the permeation pathway, we analyzed the spatial distribution of permeant ions around the gate region. This analysis selected ions located between z = –30 and –15 Å and within 10 Å of the pore axis, then we projected their coordinates onto the membrane plane. This 2D x-y distribution was normalized to its maximum value to obtain a relative probability.

DATA AVAILABILITY

The data that support this study are available from the corresponding authors upon reasonable request. The cryo-EM maps have been deposited in the Electron Microscopy Data Bank under accession codes EMD-67990 (Nav1.7V_O) and EMD-67991 (Nav1.7V_I). The corresponding atomic coordinates have been deposited in the Protein Data Bank under accession codes 21TP (Nav1.7V_O) and 21TQ (Nav1.7V_I).

[1]

Hille, B. Ion channels of excitable membranes. 3rd Edition. Sunderland: Sinauer Associates (2001).

[2]

Hodgkin, A.L. & Huxley, A.F. Resting and action potentials in single nerve fibres. J. Physiol. 104, 176–195 (1945).

[3]

Huang, J., Pan, X.J. & Yan, N. Structural biology and molecular pharmacology of voltage-gated ion channels. Nat. Rev. Mol. Cell Biol. 25, 904–925 (2024).

[4]

Liao, M.F., Cao, E.H., Julius, D. & Cheng, Y.F. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature 504, 107–112 (2013).

[5]

Kühlbrandt, W. The resolution revolution. Science 343, 1443–1444 (2014).

[6]

Shen, H.Z. et al. Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution. Science 355, eaal4326 (2017).

[7]

Yan, Z. et al. Structure of the Nav1.4-β1 complex from electric eel. Cell 170, 470–482.e11 (2017).

[8]

Pan, X.J. et al. Structure of the human voltage-gated sodium channel Nav1.4 in complex with β1. Science 362, eaau2486 (2018).

[9]

Jiang, D.H. et al. Structural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin. Nat. Commun. 12, 128 (2021).

[10]

Clairfeuille, T. et al. Structural basis of α-scorpion toxin action on Nav channels. Science 363, eaav8573 (2019).

[11]

Jiang, D.H. et al. Open-state structure and pore gating mechanism of the cardiac sodium channel. Cell 184, 5151–5162.e11 (2021).

[12]

Huang, G.X.Y. et al. Unwinding and spiral sliding of S4 and domain rotation of VSD during the electromechanical coupling in Nav1.7. Proc. Natl. Acad. Sci. USA 119, e2209164119 (2022).

[13]

Li, Z.Q. et al. Dissection of the structure-function relationship of Nav channels. Proc. Natl. Acad. Sci. USA 121, e2322899121 (2024).

[14]

Cox, J.J. et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 444, 894–898 (2006).

[15]

Cummins, T.R., Dib-Hajj, S.D. & Waxman, S.G. Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy. J. Neurosci. 24, 8232–8236 (2004).

[16]

Nassar, M.A. et al. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc. Natl. Acad. Sci. USA 101, 12706–12711 (2004).

[17]

Yang, Y. et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J. Med. Genet. 41, 171–174 (2004).

[18]

Shen, H.Z., Liu, D.L., Wu, K., Lei, J.L. & Yan, N. Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins. Science 363, 1303–1308 (2019).

[19]

Huang, G.X.Y. et al. High-resolution structures of human Nav1.7 reveal gating modulation through α-π helical transition of S6IV. Cell Rep. 39, 110735 (2022).

[20]

Zhang, J.T. et al. Structural basis for Nav1.7 inhibition by pore blockers. Nat. Struct. Mol. Biol. 291, 208–1216 (2022).

[21]

Wu, Q.R. et al. Structural mapping of Nav1.7 antagonists. Nat. Commun. 14, 3224 (2023).

[22]

Huang, J. et al. Cannabidiol inhibits Nav channels through two distinct binding sites. Nat. Commun. 14, 3613 (2023).

[23]

Huang, J., Fan, X., Jin, X.Q., Teng, L.M. & Yan, N. Dual-pocket inhibition of Nav channels by the antiepileptic drug lamotrigine. Proc. Natl. Acad. Sci. USA 120, e2309773120 (2023).

[24]

Sutro, J.B. Kinetics of veratridine action on Na channels of skeletal muscle. J. Gen. Physiol. 87, 1–24 (1986).

[25]

Leibowitz, M.D., Sutro, J.B. & Hille, B. Voltage-dependent gating of veratridine-modified Na channels. J. Gen. Physiol. 87, 25–46 (1986).

[26]

Ulbricht, W. The effect of veratridine on excitable membranes of nerve and muscle. In: Brown, L. et al. eds. Reviews of physiology, biochemistry and pharmacology 61. Berlin, Heidelberg: Springer, 18–71 (1969).

[27]

Wang, G., Dugas, M., Armah, B.I. & Honerjäger, P. Sodium channel comodification with full activator reveals veratridine reaction dynamics. Mol. Pharmacol. 37, 144–148 (1990).

[28]

Barnes, S. & Hille, B. Veratridine modifies open sodium channels. J. Gen. Physiol. 91, 421–443 (1988).

[29]

Zhang, X.Y., Bi, R.Y., Zhang, P. & Gan, Y.H. Veratridine modifies the gating of human voltage-gated sodium channel Nav1.7. Acta Pharmacol. Sin. 39, 1716–1724 (2018).

[30]

DeLano, W.L. The PyMOL molecular graphics system. https://cir.nii.ac.jp/crid/1571980075906330880 (2002).

[31]

Fan, X. et al. Phrixotoxin-3 binds to three distinct antagonistic sites on human Nav1.6. Cell Res. 35, 610–613 (2025).

[32]

Gao, S. et al. Structural basis for human Cav1.2 inhibition by multiple drugs and the neurotoxin calciseptine. Cell 186, 5363–5374.e16 (2023).

[33]

Jin, X.Q., Huang, J., Wang, H., Wang, K. & Yan, N. A versatile residue numbering scheme for Nav and Cav channels. Cell Chem. Biol. 31, 1394–1404 (2024).

[34]

Weiss, R.E. & Horn, R. Functional differences between two classes of sodium channels in developing rat skeletal muscle. Science 233, 361–364 (1986).

[35]

Liu, Y.C., Bassetto, C.A.Z. Jr., Pinto, B.I. & Bezanilla, F. A mechanistic reinterpretation of fast inactivation in voltage-gated Na+ channels. Nat. Commun. 14, 5072 (2023).

[36]

Shen, H.Z. et al. Structural basis for the modulation of voltage-gated sodium channels by animal toxins. Science 362, eaau2596 (2018).

[37]

Liu, Y. et al. Molecular basis of sodium channel inactivation. Nat. Commun. 16, 10565 (2025).

[38]

Armstrong, C.M., Bezanilla, F. & Rojas, E. Destruction of sodium conductance inactivation in squid axons perfused with pronase. J. Gen. Physiol. 62, 375–391 (1973).

[39]

West, J.W. et al. A cluster of hydrophobic amino acid residues required for fast Na+-channel inactivation. Proc. Natl. Acad. Sci. USA 89, 10910–10914 (1992).

[40]

Li, Z.Q. et al. Structure of human Nav1.5 reveals the fast inactivation-related segments as a mutational hotspot for the long QT syndrome. Proc. Natl. Acad. Sci. USA 118, e2100069118 (2021).

[41]

Pan, X.J. et al. Comparative structural analysis of human Nav1.1 and Nav1.5 reveals mutational hotspots for sodium channelopathies. Proc. Natl. Acad. Sci. USA 118, e2100066118 (2021).

[42]

Hu, R.M. et al. Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients. Channels 12, 176–186 (2018).

[43]

Itoh, H., Shimizu, M., Takata, S., Mabuchi, H. & Imoto, K. A novel missense mutation in the SCN5A gene associated with Brugada syndrome bidirectionally affecting blocking actions of antiarrhythmic drugs. J. Cardiovasc. Electrophysiol. 16, 486–493 (2005).

[44]

Huang, H., Priori, S.G., Napolitano, C., O'Leary, M.E. & Chahine, M. Y1767C, a novel SCN5A mutation, induces a persistent Na+ current and potentiates ranolazine inhibition of Nav1.5 channels. Am. J. Physiol. Heart Circ. Physiol. 300, H288–H299 (2011).

[45]

Clancy, C.E., Tateyama, M., Liu, H.J., Wehrens, X.H.T. & Kass, R.S. Non-equilibrium gating in cardiac Na+ channels: an original mechanism of arrhythmia. Circulation 107, 2233–2237 (2003).

[46]

Meng, E.C., Pettersen, E.F., Couch, G.S., Huang, C.C. & Ferrin, T.E. Tools for integrated sequence-structure analysis with UCSF Chimera. BMC Bioinformatics 7, 339 (2006).

[47]

Smart, O.S., Neduvelil, J.G., Wang, X.N., Wallace, B.A. & Sansom, M.S.P. HOLE: a program for the analysis of the pore dimensions of ion channel structural models. J. Mol. Graph. 14, 354–360 (1996).

[48]

Huang, X.S. et al. Structural basis for high-voltage activation and subtype-specific inhibition of human Nav1.8. Proc. Natl. Acad. Sci. USA 119, e2208211119 (2022).

[49]

Fan, X., Huang, J., Jin, X.Q. & Yan, N. Cryo-EM structure of human voltage-gated sodium channel Nav1.6. Proc. Natl. Acad. Sci. USA 120, e2220578120 (2023).

[50]

Tegunov, D. & Cramer, P. Real-time cryo-electron microscopy data preprocessing with Warp. Nat. Methods 16, 1146–1152 (2019).

[51]

Punjani, A., Rubinstein, J.L., Fleet, D.J. & Brubaker, M.A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017).

[52]

Emsley, P., Lohkamp, B., Scott, W.G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010).

[53]

Afonine, P.V. et al. Towards automated crystallographic structure refinement with phenix.refine. Acta Crystallogr. D Biol. Crystallogr. 68, 352–367 (2012).

[54]

Croll, T.I. ISOLDE: a physically realistic environment for model building into low-resolution electron-density maps. Acta Crystallogr. D Struct. Biol. 74, 519–530 (2018).

[55]

Jo, S., Kim, T., Iyer, V.G. & Im, W. CHARMM-GUI: a web-based graphical user interface for CHARMM. J. Comput. Chem. 29, 1859–1865 (2008).

[56]

Abraham, M.J. et al. GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1–2, 19–25 (2015).

[57]

Huang, J. et al. CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat. Methods 14, 71–73 (2017).

[58]

Bussi, G., Donadio, D. & Parrinello, M. Canonical sampling through velocity rescaling. J. Chem. Phys. 126, 014101 (2007).

[59]

Parrinello, M. & Rahman, A. Polymorphic transitions in single crystals: a new molecular dynamics method. J. Appl. Phys. 52, 7182–7190 (1981).

[60]

Darden, T., York, D. & Pedersen, L. Particle mesh Ewald: an N⋅log(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089–10092 (1993).

[61]

Hess, B., Bekker, H., Berendsen, H.J.C. & Fraaije, J.G.E.M. LINCS: a linear constraint solver for molecular simulations. J. Comput. Chem. 18, 1463–1472 (1997).

[62]

Michaud-Agrawal, N., Denning, E.J., Woolf, T.B. & Beckstein, O. MDAnalysis: a toolkit for the analysis of molecular dynamics simulations. J. Comput. Chem. 32, 2319–2327 (2011).

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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, China
4. Institute of Chemical Biology (ICB), Shenzhen Bay Laboratory, Guangming District, Shenzhen, Guangdong, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1229017484830126576, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, xref=1, ext=[AuthorCompanyExt(id=1229017484846903793, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, companyId=1229017484830126576, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. Institute of Bio-Architecture and Bio-Interactions (IBABI), Shenzhen Medical Academy of Research and Translation (SMART), Guangming District, Shenzhen, Guangdong, China)]), AuthorCompany(id=1229017484893041138, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, xref=2, ext=[AuthorCompanyExt(id=1229017484905624051, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, companyId=1229017484893041138, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=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, China)]), AuthorCompany(id=1229017485014675958, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, xref=4, ext=[AuthorCompanyExt(id=1229017485027258871, tenantId=1045748351789510663, journalId=1169329684812255232, articleId=1220387545134846830, companyId=1229017485014675958, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=4. Institute of Chemical Biology (ICB), Shenzhen Bay Laboratory, Guangming District, Shenzhen, Guangdong, China)])])]
Fan, X. et al. Open-state structure of veratridine-activated human Nav1.7 reveals the molecular choreography of fast inactivation Vita https://doi.org/10.15302/vita.2026.01.0003 ()
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