{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:48:05Z","timestamp":1789429685075,"version":"build-2803163510"},"reference-count":42,"publisher":"National Academy of Sciences","issue":"52","license":[{"start":{"date-parts":[[2020,6,10]],"date-time":"2020-06-10T00:00:00Z","timestamp":1591747200000},"content-version":"vor","delay-in-days":183,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/501100000268","name":"RCUK | Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/L006790"],"award-info":[{"award-number":["BB\/L006790"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"RCUK | Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/L02625\/21"],"award-info":[{"award-number":["BB\/L02625\/21"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"RCUK | Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["and BB\/R001294\/1"],"award-info":[{"award-number":["and BB\/R001294\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["1R56DK119709-01 4R00DK106655"],"award-info":[{"award-number":["1R56DK119709-01 4R00DK106655"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,12,26]]},"abstract":"<jats:p>Valproic acid (VPA) is an anticonvulsant drug that is also used to treat migraines and bipolar disorder. Its proposed biological targets include human voltage-gated sodium channels, among other membrane proteins. We used the prokaryotic NavMs sodium channel, which has been shown to be a good exemplar for drug binding to human sodium channels, to examine the structural and functional interactions of VPA. Thermal melt synchrotron radiation circular dichroism spectroscopic binding studies of the full-length NavMs channel (which includes both pore and voltage sensor domains), and a pore-only construct, undertaken in the presence and absence of VPA, indicated that the drug binds to and destabilizes the channel, but not the pore-only construct. This is in contrast to other antiepileptic compounds that have previously been shown to bind in the central hydrophobic core of the pore region of the channel, and that tend to increase the thermal stability of both pore-only constructs and full-length channels. Molecular docking studies also indicated that the VPA binding site is associated with the voltage sensor, rather than the hydrophobic cavity of the pore domain. Electrophysiological studies show that VPA influences the block and inactivation rates of the NavMs channel, although with lower efficacy than classical channel-blocking compounds. It thus appears that, while VPA is capable of binding to these voltage-gated sodium channels, it has a very different mode and site of action than other anticonvulsant compounds.<\/jats:p>","DOI":"10.1073\/pnas.1909696116","type":"journal-article","created":{"date-parts":[[2019,12,10]],"date-time":"2019-12-10T17:45:44Z","timestamp":1575999944000},"page":"26549-26554","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":38,"title":["Valproic acid interactions with the NavMs voltage-gated sodium channel"],"prefix":"10.1073","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0111-5347","authenticated-orcid":false,"given":"Geancarlo","family":"Zanatta","sequence":"first","affiliation":[{"name":"Institute of Structural and Molecular Biology, Birkbeck College, University of London, London WC1E 7HX, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1820-4357","authenticated-orcid":false,"given":"Altin","family":"Sula","sequence":"additional","affiliation":[{"name":"Institute of Structural and Molecular Biology, Birkbeck College, University of London, London WC1E 7HX, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2711-4174","authenticated-orcid":false,"given":"Andrew J.","family":"Miles","sequence":"additional","affiliation":[{"name":"Institute of Structural and Molecular Biology, Birkbeck College, University of London, London WC1E 7HX, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0492-5460","authenticated-orcid":false,"given":"Leo C. T.","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0765-2098","authenticated-orcid":false,"given":"Rubben","family":"Torella","sequence":"additional","affiliation":[{"name":"Inflammation and Immunology Unit, Pfizer Medicine Design, Cambridge, MA 02139;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5767-030X","authenticated-orcid":false,"given":"David C.","family":"Pryde","sequence":"additional","affiliation":[{"name":"Pfizer Worldwide Medicinal Chemistry, Great Abington, Cambridgeshire CB21 6GS, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8776-983X","authenticated-orcid":false,"given":"Paul G.","family":"DeCaen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9649-5092","authenticated-orcid":false,"given":"B. A.","family":"Wallace","sequence":"additional","affiliation":[{"name":"Institute of Structural and Molecular Biology, Birkbeck College, University of London, London WC1E 7HX, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,12,10]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"23","article-title":"Valproate in psychiatric disorders: Literature review and clinical guidelines","volume":"50","author":"McElroy S. L.","year":"1989","unstructured":"S. L. McElroy, P. E. Keck,Jr, H. G. PopeJr, J. I. Hudson, Valproate in psychiatric disorders: Literature review and clinical guidelines. J. Clin. Psychiatry 50 (suppl.), 23\u201329 (1989).","journal-title":"J. Clin. Psychiatry"},{"key":"e_1_3_4_2_2","first-page":"S57","article-title":"Rapid cycling bipolar disorder and its treatment with valproate","volume":"38","author":"Calabrese J. R.","year":"1993","unstructured":"J. R. Calabrese, D. J. Rapport, S. E. Kimmel, B. Reece, M. J. Woyshville, Rapid cycling bipolar disorder and its treatment with valproate. Can. J. Psychiatry 38 (3 suppl. 2), S57\u2013S61 (1993).","journal-title":"Can. J. Psychiatry"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/mp.2013.192","article-title":"FGF-21, a novel metabolic regulator, has a robust neuroprotective role and is markedly elevated in neurons by mood stabilizers","volume":"20","author":"Leng Y.","year":"2015","unstructured":"Y. Leng ., FGF-21, a novel metabolic regulator, has a robust neuroprotective role and is markedly elevated in neurons by mood stabilizers. Mol. Psychiatry 20, 215\u2013223 (2015).","journal-title":"Mol. Psychiatry"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"309","DOI":"10.5114\/fn.2015.56545","article-title":"Protective effect of valproic acid on cultured motor neurons under glutamate excitotoxic conditions. Ultrastructural study","volume":"53","author":"Naga\u0144ska E.","year":"2015","unstructured":"E. Naga\u0144ska, E. Matyja, A. Taraszewska, J. Rafa\u0142owska, Protective effect of valproic acid on cultured motor neurons under glutamate excitotoxic conditions. Ultrastructural study. Folia Neuropathol. 53, 309\u2013316 (2015).","journal-title":"Folia Neuropathol."},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"e11383","DOI":"10.1371\/journal.pone.0011383","article-title":"Valproate administered after traumatic brain injury provides neuroprotection and improves cognitive function in rats","volume":"5","author":"Dash P. K.","year":"2010","unstructured":"P. K. Dash ., Valproate administered after traumatic brain injury provides neuroprotection and improves cognitive function in rats. PLoS One 5, e11383 (2010).","journal-title":"PLoS One"},{"key":"e_1_3_4_6_2","first-page":"1","article-title":"Valproic acid protects primary dopamine neurons from MPP+-induced neurotoxicity: Involvement of GSK3 \u03b2 phosphorylation by Akt and ERK through the mitochondrial intrinsic apoptotic pathway","volume":"2017","author":"Zhang C.","year":"2017","unstructured":"C. Zhang ., Valproic acid protects primary dopamine neurons from MPP+-induced neurotoxicity: Involvement of GSK3 \u03b2 phosphorylation by Akt and ERK through the mitochondrial intrinsic apoptotic pathway. BioMed Res. Int. 2017, 1\u201312 (2017).","journal-title":"BioMed Res. Int."},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1002\/phar.1965","article-title":"Clinical importance of monitoring unbound valproic acid concentration in patients with hypoalbuminemia","volume":"37","author":"Dor\u00e9 M.","year":"2017","unstructured":"M. Dor\u00e9, A. E. San Juan, A. J. Frenette, D. Williamson, Clinical importance of monitoring unbound valproic acid concentration in patients with hypoalbuminemia. Pharmacotherapy 37, 900\u2013907 (2017).","journal-title":"Pharmacotherapy"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ntt.2013.01.004","article-title":"In utero exposure to valproic acid and autism\u2014a current review of clinical and animal studies","volume":"36","author":"Roullet F. I.","year":"2013","unstructured":"F. I. Roullet, J. K. Y. Lai, J. A. Foster, In utero exposure to valproic acid and autism\u2014a current review of clinical and animal studies. Neurotoxicol. Teratol. 36, 47\u201356 (2013).","journal-title":"Neurotoxicol. Teratol."},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/sj.npp.1300518","article-title":"Behavioral alterations in rats prenatally exposed to valproic acid: Animal model of autism","volume":"30","author":"Schneider T.","year":"2005","unstructured":"T. Schneider, R. Przew\u0142ocki, Behavioral alterations in rats prenatally exposed to valproic acid: Animal model of autism. Neuropsychopharmacology 30, 80\u201389 (2005).","journal-title":"Neuropsychopharmacology"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.brainres.2011.06.015","article-title":"Animal model of autism induced by prenatal exposure to valproate: Behavioral changes and liver parameters","volume":"1408","author":"Bambini-Junior V.","year":"2011","unstructured":"V. Bambini-Junior ., Animal model of autism induced by prenatal exposure to valproate: Behavioral changes and liver parameters. Brain Res. 1408, 8\u201316 (2011).","journal-title":"Brain Res."},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-0348-8759-5","volume-title":"Valproate","author":"L\u00f6scher W.","year":"1999","unstructured":"W. L\u00f6scher, \u201cThe discovery of valproate BT\u201d in Valproate, W. L\u00f6scher, Ed. (Birkh\u00e4user, Basel, 1999), pp. 1\u20133."},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/sj.mp.4001087","article-title":"Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity","volume":"7","author":"Farber N. B.","year":"2002","unstructured":"N. B. Farber, X. P. Jiang, C. Heinkel, B. Nemmers, Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. Mol. Psychiatry 7, 726\u2013733 (2002).","journal-title":"Mol. Psychiatry"},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"e22056","DOI":"10.1002\/syn.22056","article-title":"Evaluation of the antinociceptive activities of several sodium channel blockers using veratrine test in mice","volume":"72","author":"Yoshizawa K.","year":"2018","unstructured":"K. Yoshizawa ., Evaluation of the antinociceptive activities of several sodium channel blockers using veratrine test in mice. Synapse 72, e22056 (2018).","journal-title":"Synapse"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2010\/479364","article-title":"Molecular and therapeutic potential and toxicity of valproic acid","volume":"2010","author":"Chateauvieux S.","year":"2010","unstructured":"S. Chateauvieux, F. Morceau, M. Dicato, M. Diederich, Molecular and therapeutic potential and toxicity of valproic acid. J. Biomed. Biotechnol. 2010, 1\u201318 (2010).","journal-title":"J. Biomed. Biotechnol."},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1111\/j.1528-1157.1986.tb03525.x","article-title":"Valproate reduces excitability by blockage of sodium and potassium conductance","volume":"27","author":"VanDongen A. M.","year":"1986","unstructured":"A. M. VanDongen, M. G. VanErp, R. A. Voskuyl, Valproate reduces excitability by blockage of sodium and potassium conductance. Epilepsia 27, 177\u2013182 (1986).","journal-title":"Epilepsia"},{"key":"e_1_3_4_16_2","first-page":"1001","article-title":"Sodium valproate, but not ethosuximide, produces use- and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture","volume":"237","author":"McLean M. J.","year":"1986","unstructured":"M. J. McLean, R. L. Macdonald, Sodium valproate, but not ethosuximide, produces use- and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture. J. Pharmacol. Exp. Ther. 237, 1001\u20131011 (1986).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/BF00228121","article-title":"Effects induced by the antiepileptic drug valproic acid upon the ionic currents recorded in rat neocortical neurons in cell culture","volume":"81","author":"Zona C.","year":"1990","unstructured":"C. Zona, M. Avoli, Effects induced by the antiepileptic drug valproic acid upon the ionic currents recorded in rat neocortical neurons in cell culture. Exp. Brain Res. 81, 313\u2013317 (1990).","journal-title":"Exp. Brain Res."},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/S0920-1211(98)00060-6","article-title":"Valproate selectively reduces the persistent fraction of Na+ current in neocortical neurons","volume":"32","author":"Taverna S.","year":"1998","unstructured":"S. Taverna, M. Mantegazza, S. Franceschetti, G. Avanzini, Valproate selectively reduces the persistent fraction of Na+ current in neocortical neurons. Epilepsy Res. 32, 304\u2013308 (1998).","journal-title":"Epilepsy Res."},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1046\/j.1460-9568.2003.02710.x","article-title":"Anticonvulsant pharmacology of voltage-gated Na+ channels in hippocampal neurons of control and chronically epileptic rats","volume":"17","author":"Remy S.","year":"2003","unstructured":"S. Remy, B. W. Urban, C. E. Elger, H. Beck, Anticonvulsant pharmacology of voltage-gated Na+ channels in hippocampal neurons of control and chronically epileptic rats. Eur. J. Neurosci. 17, 2648\u20132658 (2003).","journal-title":"Eur. J. Neurosci."},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.bbrc.2017.07.109","article-title":"Valproic acid inhibits TTX-resistant sodium currents in prefrontal cortex pyramidal neurons","volume":"491","author":"Szulczyk B.","year":"2017","unstructured":"B. Szulczyk, E. Nurowska, Valproic acid inhibits TTX-resistant sodium currents in prefrontal cortex pyramidal neurons. Biochem. Biophys. Res. Commun. 491, 291\u2013295 (2017).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"14205","DOI":"10.1038\/ncomms14205","article-title":"The complete structure of an activated open sodium channel","volume":"8","author":"Sula A.","year":"2017","unstructured":"A. Sula ., The complete structure of an activated open sodium channel. Nat. Commun. 8, 14205 (2017).","journal-title":"Nat. Commun."},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1085\/jgp.201611740","article-title":"Interpreting the functional role of a novel interaction motif in prokaryotic sodium channels","volume":"149","author":"Sula A.","year":"2017","unstructured":"A. Sula, B. A. Wallace, Interpreting the functional role of a novel interaction motif in prokaryotic sodium channels. J. Gen. Physiol. 149, 613\u2013622 (2017).","journal-title":"J. Gen. Physiol."},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"8428","DOI":"10.1073\/pnas.1406855111","article-title":"Prokaryotic NavMs channel as a structural and functional model for eukaryotic sodium channel antagonism","volume":"111","author":"Bagn\u00e9ris C.","year":"2014","unstructured":"C. Bagn\u00e9ris ., Prokaryotic NavMs channel as a structural and functional model for eukaryotic sodium channel antagonism. Proc. Natl. Acad. Sci. U.S.A. 111, 8428\u20138433 (2014).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1085\/jgp.69.4.497","article-title":"Local anesthetics: Hydrophilic and hydrophobic pathways for the drug-receptor reaction","volume":"69","author":"Hille B.","year":"1977","unstructured":"B. Hille, Local anesthetics: Hydrophilic and hydrophobic pathways for the drug-receptor reaction. J. Gen. Physiol. 69, 497\u2013515 (1977).","journal-title":"J. Gen. Physiol."},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1042\/BST20180295","article-title":"Comparisons of voltage-gated sodium channel structures with open and closed gates and implications for state-dependent drug design","volume":"46","author":"Montini G.","year":"2018","unstructured":"G. Montini, J. Booker, A. Sula, B. A. Wallace, Comparisons of voltage-gated sodium channel structures with open and closed gates and implications for state-dependent drug design. Biochem. Soc. Trans. 46, 1567\u20131575 (2018).","journal-title":"Biochem. Soc. Trans."},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1016\/j.bbamem.2009.02.005","article-title":"Thermal and chemical unfolding and refolding of a eukaryotic sodium channel","volume":"1788","author":"Charalambous K.","year":"2009","unstructured":"K. Charalambous, A. O. O\u2019Reilly, P. A. Bullough, B. A. Wallace, Thermal and chemical unfolding and refolding of a eukaryotic sodium channel. Biochim. Biophys. Acta 1788, 1279\u20131286 (2009).","journal-title":"Biochim. Biophys. Acta"},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1080\/09687680802508754","article-title":"G219S mutagenesis as a means of stabilizing conformational flexibility in the bacterial sodium channel NaChBac","volume":"25","author":"O\u2019Reilly A. O.","year":"2008","unstructured":"A. O. O\u2019Reilly, K. Charalambous, G. Nurani, A. M. Powl, B. A. Wallace, G219S mutagenesis as a means of stabilizing conformational flexibility in the bacterial sodium channel NaChBac. Mol. Membr. Biol. 25, 670\u2013676 (2008).","journal-title":"Mol. Membr. Biol."},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"e23067","DOI":"10.1002\/bip.23067","article-title":"Thermal melt circular dichroism spectroscopic studies for identifying stabilising amphipathic molecules for the voltage-gated sodium channel NavMs","volume":"109","author":"Ireland S. M.","year":"2018","unstructured":"S. M. Ireland, A. Sula, B. A. Wallace, Thermal melt circular dichroism spectroscopic studies for identifying stabilising amphipathic molecules for the voltage-gated sodium channel NavMs. Biopolymers 109, e23067 (2018).","journal-title":"Biopolymers"},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/j.bbamem.2011.12.019","article-title":"Transmembrane and extramembrane contributions to membrane protein thermal stability: Studies with the NaChBac sodium channel","volume":"1818","author":"Powl A. M.","year":"2012","unstructured":"A. M. Powl, A. J. Miles, B. A. Wallace, Transmembrane and extramembrane contributions to membrane protein thermal stability: Studies with the NaChBac sodium channel. Biochim. Biophys. Acta Biomembr. 1818, 889\u2013895 (2012).","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1042\/bst0310631","article-title":"Circular dichroism and synchrotron radiation circular dichroism spectroscopy: Tools for drug discovery","volume":"31","author":"Wallace B. A.","year":"2003","unstructured":"B. A. Wallace, R. W. Janes, Circular dichroism and synchrotron radiation circular dichroism spectroscopy: Tools for drug discovery. Biochem. Soc. Trans. 31, 631\u2013633 (2003).","journal-title":"Biochem. Soc. Trans."},{"key":"e_1_3_4_31_2","doi-asserted-by":"crossref","first-page":"4859","DOI":"10.1039\/C5CS00084J","article-title":"Circular dichroism spectroscopy of membrane proteins","volume":"45","author":"Miles A. J.","year":"2016","unstructured":"A. J. Miles, B. A. Wallace, Circular dichroism spectroscopy of membrane proteins. Chem. Soc. Rev. 45, 4859\u20134872 (2016).","journal-title":"Chem. Soc. Rev."},{"key":"e_1_3_4_32_2","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/nature18615","article-title":"Toremifene interacts with and destabilizes the Ebola virus glycoprotein","volume":"535","author":"Zhao Y.","year":"2016","unstructured":"Y. Zhao ., Toremifene interacts with and destabilizes the Ebola virus glycoprotein. Nature 535, 169\u2013172 (2016).","journal-title":"Nature"},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/nchembio.2070","article-title":"A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate","volume":"12","author":"Pacold M. E.","year":"2016","unstructured":"M. E. Pacold ., A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat. Chem. Biol. 12, 452\u2013458 (2016).","journal-title":"Nat. Chem. Biol."},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","first-page":"aac5464","DOI":"10.1126\/science.aac5464","article-title":"Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist","volume":"350","author":"Ahuja S.","year":"2015","unstructured":"S. Ahuja ., Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist. Science 350, aac5464 (2015).","journal-title":"Science"},{"key":"e_1_3_4_35_2","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/j.clinbiochem.2013.06.012","article-title":"Adverse drug reactions induced by valproic acid","volume":"46","author":"Nanau R. M.","year":"2013","unstructured":"R. M. Nanau, M. G. Neuman, Adverse drug reactions induced by valproic acid. Clin. Biochem. 46, 1323\u20131338 (2013).","journal-title":"Clin. Biochem."},{"key":"e_1_3_4_36_2","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1038\/ncomms2077","article-title":"Structure of a bacterial voltage-gated sodium channel pore reveals mechanisms of opening and closing","volume":"3","author":"McCusker E. C.","year":"2012","unstructured":"E. C. McCusker ., Structure of a bacterial voltage-gated sodium channel pore reveals mechanisms of opening and closing. Nat. Commun. 3, 1102 (2012).","journal-title":"Nat. Commun."},{"key":"e_1_3_4_37_2","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1038\/nprot.2016.051","article-title":"Computational protein-ligand docking and virtual drug screening with the AutoDock suite","volume":"11","author":"Forli S.","year":"2016","unstructured":"S. Forli ., Computational protein-ligand docking and virtual drug screening with the AutoDock suite. Nat. Protoc. 11, 905\u2013919 (2016).","journal-title":"Nat. Protoc."},{"key":"e_1_3_4_38_2","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1126\/science.aaw2999","article-title":"Molecular basis for pore blockade of human Na+ channel Nav1.2 by the \u03bc-conotoxin KIIIA","volume":"363","author":"Pan X.","year":"2019","unstructured":"X. Pan ., Molecular basis for pore blockade of human Na+ channel Nav1.2 by the \u03bc-conotoxin KIIIA. Science 363, 1309\u20131313 (2019).","journal-title":"Science"},{"key":"e_1_3_4_39_2","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1002\/pro.3474","article-title":"CDtoolX, a downloadable software package for processing and analyses of circular dichroism spectroscopic data","volume":"27","author":"Miles A. J.","year":"2018","unstructured":"A. J. Miles, B. A. Wallace, CDtoolX, a downloadable software package for processing and analyses of circular dichroism spectroscopic data. Protein Sci. 27, 1717\u20131722 (2018).","journal-title":"Protein Sci."},{"key":"e_1_3_4_40_2","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1002\/bip.20853","article-title":"Protein secondary structure analyses from circular dichroism spectroscopy: Methods and reference databases","volume":"89","author":"Whitmore L.","year":"2008","unstructured":"L. Whitmore, B. A. Wallace, Protein secondary structure analyses from circular dichroism spectroscopy: Methods and reference databases. Biopolymers 89, 392\u2013400 (2008).","journal-title":"Biopolymers"},{"key":"e_1_3_4_41_2","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkq1026","article-title":"PCDDB: The Protein Circular Dichroism Data Bank, a repository for circular dichroism spectral and metadata","volume":"39","author":"Whitmore L.","year":"2011","unstructured":"L. Whitmore ., PCDDB: The Protein Circular Dichroism Data Bank, a repository for circular dichroism spectral and metadata. Nucleic Acids Res. 39, D480\u2013D486 (2011).","journal-title":"Nucleic Acids Res."},{"key":"e_1_3_4_42_2","doi-asserted-by":"crossref","first-page":"D303","DOI":"10.1093\/nar\/gkw796","article-title":"PCDDB: New developments at the Protein Circular Dichroism Data Bank","volume":"45","author":"Whitmore L.","year":"2017","unstructured":"L. Whitmore, A. J. Miles, L. Mavridis, R. W. Janes, B. A. Wallace, PCDDB: New developments at the Protein Circular Dichroism Data Bank. Nucleic Acids Res. 45, D303\u2013D307 (2017).","journal-title":"Nucleic Acids Res."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.1909696116","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1909696116","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T17:36:02Z","timestamp":1654623362000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1909696116"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,10]]},"references-count":42,"journal-issue":{"issue":"52","published-print":{"date-parts":[[2019,12,26]]}},"alternative-id":["10.1073\/pnas.1909696116"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1909696116","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,10]]},"assertion":[{"value":"2019-12-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}