{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:18:24Z","timestamp":1790381904820,"version":"4.1.0"},"reference-count":89,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T00:00:00Z","timestamp":1718755200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T00:00:00Z","timestamp":1718755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Struct Mol Biol"],"published-print":{"date-parts":[[2024,12]]},"DOI":"10.1038\/s41594-024-01335-1","type":"journal-article","created":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T10:02:20Z","timestamp":1718791340000},"page":"1964-1974","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Structures of synaptic vesicle protein 2A and 2B bound to anticonvulsants"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0478-2682","authenticated-orcid":false,"given":"Anshumali","family":"Mittal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4298-1604","authenticated-orcid":false,"given":"Matthew F.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena J.","family":"Levin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Provins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Procter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Ledecq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Hillisch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Wolff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Gillard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2218-9986","authenticated-orcid":false,"given":"Peter S.","family":"Horanyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0001-6195","authenticated-orcid":false,"given":"Jonathan A.","family":"Coleman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,19]]},"reference":[{"key":"1335_CR1","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1056\/NEJMra022308","volume":"349","author":"BS Chang","year":"2003","unstructured":"Chang, B. S. & Lowenstein, D. H. Epilepsy. N. Engl. J. Med. 349, 1257\u20131266 (2003).","journal-title":"N. Engl. J. Med."},{"key":"1335_CR2","unstructured":"World Health Organization. Epilepsy. https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/epilepsy (2023)."},{"key":"1335_CR3","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.eplepsyres.2009.03.003","volume":"85","author":"PN Banerjee","year":"2009","unstructured":"Banerjee, P. N., Filippi, D. & Hauser, W. A. The descriptive epidemiology of epilepsy\u2014a review. Epilepsy Res. 85, 31\u201345 (2009).","journal-title":"Epilepsy Res."},{"key":"1335_CR4","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1007\/s40263-021-00827-8","volume":"35","author":"W L\u00f6scher","year":"2021","unstructured":"L\u00f6scher, W. & Klein, P. The pharmacology and clinical efficacy of antiseizure medications: from bromide salts to cenobamate and beyond. CNS Drugs 35, 935\u2013963 (2021).","journal-title":"CNS Drugs"},{"key":"1335_CR5","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1083\/jcb.100.4.1284","volume":"100","author":"K Buckley","year":"1985","unstructured":"Buckley, K. & Kelly, R. B. Identification of a transmembrane glycoprotein specific for secretory vesicles of neural and endocrine cells. J. Cell Biol. 100, 1284\u20131294 (1985).","journal-title":"J. Cell Biol."},{"key":"1335_CR6","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1016\/j.cell.2006.10.030","volume":"127","author":"S Takamori","year":"2006","unstructured":"Takamori, S. et al. Molecular anatomy of a trafficking organelle. Cell 127, 831\u2013846 (2006).","journal-title":"Cell"},{"key":"1335_CR7","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaa183","volume":"2","author":"P Muglia","year":"2020","unstructured":"Muglia, P. et al. Padsevonil randomized Phase IIa trial in treatment-resistant focal epilepsy: a translational approach. Brain Commun. 2, fcaa183 (2020).","journal-title":"Brain Commun."},{"key":"1335_CR8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1124\/jpet.119.261149","volume":"372","author":"M Wood","year":"2020","unstructured":"Wood, M. et al. Pharmacological profile of the novel antiepileptic drug candidate padsevonil: interactions with synaptic vesicle 2 proteins and the GABAA receptor. J. Pharmacol. Exp. Ther. 372, 1\u201310 (2020).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"1335_CR9","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1002\/epi4.12656","volume":"7","author":"M Rademacher","year":"2022","unstructured":"Rademacher, M. et al. Efficacy and safety of adjunctive padsevonil in adults with drug\u2010resistant focal epilepsy: results from two double\u2010blind, randomized, placebo\u2010controlled trials. Epilepsia Open 7, 758 (2022).","journal-title":"Epilepsia Open"},{"key":"1335_CR10","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/0092-8674(92)90319-8","volume":"70","author":"MB Feany","year":"1992","unstructured":"Feany, M. B., Lee, S., Edwards, R. H. & Buckley, K. M. The synaptic vesicle protein SV2 is a novel type of transmembrane transporter. Cell 70, 861\u2013867 (1992).","journal-title":"Cell"},{"key":"1335_CR11","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/0378-1119(93)90024-W","volume":"137","author":"PS Bindra","year":"1993","unstructured":"Bindra, P. S., Knowles, R. & Buckley, K. M. Conservation of the amino acid sequence of SV2, a transmembrane transporter in synaptic vesicles and endocrine cells. Gene 137, 299\u2013302 (1993).","journal-title":"Gene"},{"key":"1335_CR12","doi-asserted-by":"publisher","first-page":"2150","DOI":"10.1073\/pnas.90.6.2150","volume":"90","author":"SM Bajjalieh","year":"1993","unstructured":"Bajjalieh, S. M., Peterson, K., Linial, M. & Scheller, R. H. Brain contains two forms of synaptic vesicle protein 2. Proc. Natl Acad. Sci. USA 90, 2150\u20132154 (1993).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1335_CR13","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.mcn.2004.12.011","volume":"29","author":"AE Schivell","year":"2005","unstructured":"Schivell, A. E., Mochida, S., Kensel-Hammes, P., Custer, K. L. & Bajjalieh, S. M. SV2A and SV2C contain a unique synaptotagmin-binding site. Mol. Cell. Neurosci. 29, 56\u201364 (2005).","journal-title":"Mol. Cell. Neurosci."},{"key":"1335_CR14","doi-asserted-by":"publisher","first-page":"27770","DOI":"10.1074\/jbc.271.44.27770","volume":"271","author":"AE Schivell","year":"1996","unstructured":"Schivell, A. E., Batchelor, R. H. & Bajjalieh, S. M. Isoform-specific, calcium-regulated interaction of the synaptic vesicle proteins SV2 and synaptotagmin. J. Biol. Chem. 271, 27770\u201327775 (1996).","journal-title":"J. Biol. Chem."},{"key":"1335_CR15","doi-asserted-by":"publisher","first-page":"52124","DOI":"10.1074\/jbc.M407502200","volume":"279","author":"DR Lazzell","year":"2004","unstructured":"Lazzell, D. R., Belizaire, R., Thakur, P., Sherry, D. M. & Janz, R. SV2B regulates synaptotagmin 1 by direct interaction. J. Biol. Chem. 279, 52124\u201352131 (2004).","journal-title":"J. Biol. Chem."},{"key":"1335_CR16","doi-asserted-by":"publisher","first-page":"7297","DOI":"10.1073\/pnas.1501627112","volume":"112","author":"N Kaempf","year":"2015","unstructured":"Kaempf, N. et al. Overlapping functions of stonin 2 and SV2 in sorting of the calcium sensor synaptotagmin 1 to synaptic vesicles. Proc. Natl Acad. Sci. USA 112, 7297\u20137302 (2015).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1335_CR17","doi-asserted-by":"publisher","first-page":"4586","DOI":"10.1523\/JNEUROSCI.0210-20.2020","volume":"40","author":"CB Harper","year":"2020","unstructured":"Harper, C. B. et al. An epilepsy-associated SV2A mutation disrupts synaptotagmin-1 expression and activity-dependent trafficking. J. Neurosci. 40, 4586\u20134595 (2020).","journal-title":"J. Neurosci."},{"key":"1335_CR18","doi-asserted-by":"publisher","first-page":"2492","DOI":"10.1523\/JNEUROSCI.4248-14.2015","volume":"35","author":"N Zhang","year":"2015","unstructured":"Zhang, N. et al. Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1. J. Neurosci. 35, 2492\u20132507 (2015).","journal-title":"J. Neurosci."},{"key":"1335_CR19","doi-asserted-by":"publisher","first-page":"e57154","DOI":"10.7554\/eLife.57154","volume":"9","author":"R Voleti","year":"2020","unstructured":"Voleti, R., Jaczynska, K. & Rizo, J. Ca2+-dependent release of synaptotagmin-1 from the SNARE complex on phosphatidylinositol 4,5-bisphosphate-containing membranes. eLife 9, e57154 (2020).","journal-title":"eLife"},{"key":"1335_CR20","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1038\/nature14975","volume":"525","author":"Q Zhou","year":"2015","unstructured":"Zhou, Q. et al. Architecture of the synaptotagmin\u2013SNARE machinery for neuronal exocytosis. Nature 525, 62\u201367 (2015).","journal-title":"Nature"},{"key":"1335_CR21","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1038\/nm.3338","volume":"19","author":"TC S\u00fcdhof","year":"2013","unstructured":"S\u00fcdhof, T. C. A molecular machine for neurotransmitter release: synaptotagmin and beyond. Nat. Med. 19, 1227\u20131231 (2013).","journal-title":"Nat. Med."},{"key":"1335_CR22","doi-asserted-by":"publisher","first-page":"33066","DOI":"10.1074\/jbc.C114.584516","volume":"289","author":"M Madeo","year":"2014","unstructured":"Madeo, M., Kov\u00e1cs, A. D. & Pearce, D. A. The human synaptic vesicle protein, SV2A, functions as a galactose transporter in Saccharomyces cerevisiae. J. Biol. Chem. 289, 33066\u201333071 (2014).","journal-title":"J. Biol. Chem."},{"key":"1335_CR23","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.semcdb.2019.02.003","volume":"95","author":"K Ciruelas","year":"2019","unstructured":"Ciruelas, K., Marcotulli, D. & Bajjalieh, S. M. Synaptic vesicle protein 2: a multi-faceted regulator of secretion. Semin. Cell Dev. Biol. 95, 130\u2013141 (2019).","journal-title":"Semin. Cell Dev. Biol."},{"key":"1335_CR24","doi-asserted-by":"publisher","first-page":"5223","DOI":"10.1523\/JNEUROSCI.14-09-05223.1994","volume":"14","author":"SM Bajjalieh","year":"1994","unstructured":"Bajjalieh, S. M., Frantz, G. D., Weimann, J. M., McConnell, S. K. & Scheller, R. H. Differential expression of synaptic vesicle protein 2 (SV2) isoforms. J. Neurosci. 14, 5223\u20135235 (1994).","journal-title":"J. Neurosci."},{"key":"1335_CR25","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1016\/S0896-6273(00)81046-6","volume":"24","author":"R Janz","year":"1999","unstructured":"Janz, R., Goda, Y., Geppert, M., Missler, M. & S\u00fcdhof, T. C. SV2A and SV2B function as redundant Ca2+ regulators in neurotransmitter release. Neuron 24, 1003\u20131016 (1999).","journal-title":"Neuron"},{"key":"1335_CR26","doi-asserted-by":"publisher","unstructured":"Paulussen, I. et al. SV2B defines a subpopulation of synaptic vesicles. J. Mol. Cell Biol. https:\/\/doi.org\/10.1093\/jmcb\/mjad054 (2023).","DOI":"10.1093\/jmcb\/mjad054"},{"key":"1335_CR27","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.brainres.2010.09.063","volume":"1367","author":"D Dardou","year":"2011","unstructured":"Dardou, D. et al. Distribution of SV2C mRNA and protein expression in the mouse brain with a particular emphasis on the basal ganglia system. Brain Res. 1367, 130\u2013145 (2011).","journal-title":"Brain Res."},{"key":"1335_CR28","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-14-87","volume":"14","author":"J Cr\u00e8vec\u0153ur","year":"2013","unstructured":"Cr\u00e8vec\u0153ur, J. et al. Expression of SV2 isoforms during rodent brain development. BMC Neurosci. 14, 87 (2013).","journal-title":"BMC Neurosci."},{"key":"1335_CR29","doi-asserted-by":"publisher","first-page":"15268","DOI":"10.1073\/pnas.96.26.15268","volume":"96","author":"KM Crowder","year":"1999","unstructured":"Crowder, K. M. et al. Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A). Proc. Natl Acad. Sci. USA 96, 15268\u201315273 (1999).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1335_CR30","doi-asserted-by":"publisher","first-page":"100425","DOI":"10.1016\/j.ebr.2020.100425","volume":"15","author":"DG Calame","year":"2021","unstructured":"Calame, D. G., Herman, I. & Riviello, J. J. A de novo heterozygous rare variant in SV2A causes epilepsy and levetiracetam-induced drug-resistant status epilepticus. Epilepsy Behav. Rep. 15, 100425 (2021).","journal-title":"Epilepsy Behav. Rep."},{"key":"1335_CR31","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1016\/j.pediatrneurol.2015.02.011","volume":"52","author":"FJ Serajee","year":"2015","unstructured":"Serajee, F. J. & Huq, A. M. Homozygous mutation in synaptic vesicle glycoprotein 2A gene results in intractable epilepsy, involuntary movements, microcephaly, and developmental and growth retardation. Pediatr. Neurol. 52, 642\u2013646.e1 (2015).","journal-title":"Pediatr. Neurol."},{"key":"1335_CR32","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.clineuro.2019.03.020","volume":"181","author":"D Wang","year":"2019","unstructured":"Wang, D. et al. Levetiracetam-induced a new seizure type in a girl with a novel SV2A gene mutation. Clin. Neurol. Neurosurg. 181, 64\u201366 (2019).","journal-title":"Clin. Neurol. Neurosurg."},{"key":"1335_CR33","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-37860-8","volume":"14","author":"Z Liu","year":"2023","unstructured":"Liu, Z. et al. Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2. Nat. Commun. 14, 2338 (2023).","journal-title":"Nat. Commun."},{"key":"1335_CR34","doi-asserted-by":"publisher","first-page":"153","DOI":"10.3390\/toxins10040153","volume":"10","author":"R Gustafsson","year":"2018","unstructured":"Gustafsson, R., Zhang, S., Masuyer, G., Dong, M. & Stenmark, P. Crystal structure of botulinum neurotoxin A2 in complex with the human protein receptor SV2C reveals plasticity in receptor binding. Toxins 10, 153 (2018).","journal-title":"Toxins"},{"key":"1335_CR35","doi-asserted-by":"publisher","unstructured":"Ciruelas, K., Marcotulli, D., Sullivan, J. M. & Bajjalieh, S. M. Levetiracetam inhibits SV2A-synaptotagmin interaction at synapses that lack SV2B. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/640185 (2019).","DOI":"10.1101\/640185"},{"key":"1335_CR36","doi-asserted-by":"publisher","first-page":"C960","DOI":"10.1152\/ajpcell.00259.2010","volume":"299","author":"A Nowack","year":"2010","unstructured":"Nowack, A., Yao, J., Custer, K. L. & Bajjalieh, S. M. SV2 regulates neurotransmitter release via multiple mechanisms. Am. J. Physiol. Cell Physiol. 299, C960\u2013C967 (2010).","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"1335_CR37","doi-asserted-by":"publisher","first-page":"e0116589","DOI":"10.1371\/journal.pone.0116589","volume":"10","author":"J Lee","year":"2015","unstructured":"Lee, J. et al. Exploring the interaction of SV2A with racetams using homology modelling, molecular dynamics and site-directed mutagenesis. PLoS ONE 10, e0116589 (2015).","journal-title":"PLoS ONE"},{"key":"1335_CR38","doi-asserted-by":"publisher","first-page":"777","DOI":"10.2967\/jnumed.115.168179","volume":"57","author":"NB Nabulsi","year":"2016","unstructured":"Nabulsi, N. B. et al. Synthesis and preclinical evaluation of 11C-UCB-J as a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the brain. J. Nucl. Med. 57, 777\u2013784 (2016).","journal-title":"J. Nucl. Med."},{"key":"1335_CR39","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1126\/science.1123654","volume":"312","author":"M Dong","year":"2006","unstructured":"Dong, M. et al. SV2 is the protein receptor for botulinum neurotoxin A. Science 312, 592\u2013596 (2006).","journal-title":"Science"},{"key":"1335_CR40","doi-asserted-by":"publisher","first-page":"e1001207","DOI":"10.1371\/journal.ppat.1001207","volume":"6","author":"FL Yeh","year":"2010","unstructured":"Yeh, F. L. et al. SV2 mediates entry of tetanus neurotoxin into central neurons. PLoS Pathog. 6, e1001207 (2010).","journal-title":"PLoS Pathog."},{"key":"1335_CR41","doi-asserted-by":"publisher","first-page":"5226","DOI":"10.1091\/mbc.e08-07-0765","volume":"19","author":"M Dong","year":"2008","unstructured":"Dong, M. et al. Glycosylated SV2A and SV2B mediate the entry of botulinum neurotoxin E into neurons. Mol. Biol. Cell 19, 5226\u20135237 (2008).","journal-title":"Mol. Biol. Cell"},{"key":"1335_CR42","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1038\/nsmb.3245","volume":"23","author":"G Yao","year":"2016","unstructured":"Yao, G. et al. N-linked glycosylation of SV2 is required for binding and uptake of botulinum neurotoxin A. Nat. Struct. Mol. Biol. 23, 656\u2013662 (2016).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"1335_CR43","doi-asserted-by":"publisher","first-page":"35658","DOI":"10.1074\/jbc.M112.398883","volume":"287","author":"SE Kwon","year":"2012","unstructured":"Kwon, S. E. & Chapman, E. R. Glycosylation is dispensable for sorting of synaptotagmin 1 but is critical for targeting of SV2 and synaptophysin to recycling synaptic vesicles. J. Biol. Chem. 287, 35658\u201335668 (2012).","journal-title":"J. Biol. Chem."},{"key":"1335_CR44","doi-asserted-by":"publisher","first-page":"3485","DOI":"10.1073\/pnas.0336914100","volume":"100","author":"D Reigada","year":"2003","unstructured":"Reigada, D. et al. Control of neurotransmitter release by an internal gel matrix in synaptic vesicles. Proc. Natl Acad. Sci. USA 100, 3485\u20133490 (2003).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1335_CR45","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1038\/s41594-023-01017-4","volume":"30","author":"Y Suo","year":"2023","unstructured":"Suo, Y. et al. Molecular basis of polyspecific drug and xenobiotic recognition by OCT1 and OCT2. Nat. Struct. Mol. Biol. 30, 1001\u20131011 (2023).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"1335_CR46","doi-asserted-by":"publisher","unstructured":"Parker, J. L., Kato, T., Kuteyi, G., Sitsel, O. & Newstead, S. Molecular basis for selective uptake and elimination of organic anions in the kidney by OAT1. Nat. Struct. Mol. Biol. https:\/\/doi.org\/10.1038\/s41594-023-01039-y (2023).","DOI":"10.1038\/s41594-023-01039-y"},{"key":"1335_CR47","doi-asserted-by":"publisher","first-page":"W368","DOI":"10.1093\/nar\/gky309","volume":"46","author":"L Pravda","year":"2018","unstructured":"Pravda, L. et al. MOLEonline: a web-based tool for analyzing channels, tunnels and pores (2018 update). Nucleic Acids Res. 46, W368\u2013W373 (2018).","journal-title":"Nucleic Acids Res."},{"key":"1335_CR48","doi-asserted-by":"publisher","first-page":"5289","DOI":"10.1021\/acs.chemrev.0c00983","volume":"121","author":"D Drew","year":"2021","unstructured":"Drew, D., North, R. A., Nagarathinam, K. & Tanabe, M. Structures and general transport mechanisms by the major facilitator superfamily (MFS). Chem. Rev. 121, 5289\u20135335 (2021).","journal-title":"Chem. Rev."},{"key":"1335_CR49","doi-asserted-by":"publisher","first-page":"2695","DOI":"10.1021\/ja512751q","volume":"137","author":"L Wang","year":"2015","unstructured":"Wang, L. et al. Accurate and reliable prediction of relative ligand binding potency in prospective drug discovery by way of a modern free-energy calculation protocol and force field. J. Am. Chem. Soc. 137, 2695\u20132703 (2015).","journal-title":"J. Am. Chem. Soc."},{"key":"1335_CR50","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.1021\/acs.accounts.7b00083","volume":"50","author":"R Abel","year":"2017","unstructured":"Abel, R., Wang, L., Harder, E. D., Berne, B. J. & Friesner, R. A. Advancing drug discovery through enhanced free energy calculations. Acc. Chem. Res. 50, 1625\u20131632 (2017).","journal-title":"Acc. Chem. Res."},{"key":"1335_CR51","doi-asserted-by":"publisher","first-page":"3171","DOI":"10.1021\/acs.jcim.3c00013","volume":"63","author":"W Chen","year":"2023","unstructured":"Chen, W. et al. Enhancing hit discovery in virtual screening through absolute protein-ligand binding free-energy calculations. J. Chem. Inf. Model. 63, 3171\u20133185 (2023).","journal-title":"J. Chem. Inf. Model."},{"key":"1335_CR52","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1042\/BST0391341","volume":"39","author":"J Shi","year":"2011","unstructured":"Shi, J. et al. Combining modelling and mutagenesis studies of synaptic vesicle protein 2A to identify a series of residues involved in racetam binding. Biochem. Soc. Trans. 39, 1341\u20131347 (2011).","journal-title":"Biochem. Soc. Trans."},{"key":"1335_CR53","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.conb.2020.04.006","volume":"63","author":"AC Wolfes","year":"2020","unstructured":"Wolfes, A. C. & Dean, C. The diversity of synaptotagmin isoforms. Curr. Opin. Neurobiol. 63, 198\u2013209 (2020).","journal-title":"Curr. Opin. Neurobiol."},{"key":"1335_CR54","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1016\/j.seizure.2009.07.004","volume":"18","author":"X-F Yang","year":"2009","unstructured":"Yang, X.-F. & Rothman, S. M. Levetiracetam has a time- and stimulation-dependent effect on synaptic transmission. Seizure 18, 615\u2013619 (2009).","journal-title":"Seizure"},{"key":"1335_CR55","doi-asserted-by":"publisher","first-page":"1899","DOI":"10.1111\/epi.13223","volume":"56","author":"X Yang","year":"2015","unstructured":"Yang, X. et al. Brivaracetam augments short-term depression and slows vesicle recycling. Epilepsia 56, 1899\u20131909 (2015).","journal-title":"Epilepsia"},{"key":"1335_CR56","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.bbrc.2008.07.145","volume":"375","author":"BA Lynch","year":"2008","unstructured":"Lynch, B. A. et al. Visualization of SV2A conformations in situ by the use of protein tomography. Biochem. Biophys. Res. Commun. 375, 491\u2013495 (2008).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"1335_CR57","doi-asserted-by":"publisher","first-page":"2577","DOI":"10.1016\/j.bpj.2009.08.032","volume":"97","author":"KL Budzinski","year":"2009","unstructured":"Budzinski, K. L. et al. Large structural change in isolated synaptic vesicles upon loading with neurotransmitter. Biophys. J. 97, 2577\u20132584 (2009).","journal-title":"Biophys. J."},{"key":"1335_CR58","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1111\/bph.12192","volume":"169","author":"V Daniels","year":"2013","unstructured":"Daniels, V., Wood, M., Leclercq, K., Kaminski, R. M. & Gillard, M. Modulation of the conformational state of the SV2A protein by an allosteric mechanism as evidenced by ligand binding assays. Br. J. Pharmacol. 169, 1091\u20131101 (2013).","journal-title":"Br. J. Pharmacol."},{"key":"1335_CR59","doi-asserted-by":"publisher","first-page":"e147","DOI":"10.1111\/epi.14532","volume":"59","author":"MD Wood","year":"2018","unstructured":"Wood, M. D., Sands, Z. A., Vandenplas, C. & Gillard, M. Further evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein. Epilepsia 59, e147\u2013e151 (2018).","journal-title":"Epilepsia"},{"key":"1335_CR60","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1111\/epi.13638","volume":"58","author":"MD Wood","year":"2017","unstructured":"Wood, M. D. & Gillard, M. Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein. Epilepsia 58, 255\u2013262 (2017).","journal-title":"Epilepsia"},{"key":"1335_CR61","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.1066447","volume":"13","author":"W Botermans","year":"2023","unstructured":"Botermans, W. et al. SDI-118, a novel procognitive SV2A modulator: first-in-human randomized controlled trial including PET\/fMRI assessment of target engagement. Front. Pharm. 13, 1066447 (2023).","journal-title":"Front. Pharm."},{"key":"1335_CR62","unstructured":"Provins, L. & Quesnel, Y. 2-oxo-1-imidazolidinyl imidazothiadiazole derivatives. Publication number WO2012\/143117, international application number PCT\/EP2012\/001658 (2012)."},{"key":"1335_CR63","unstructured":"Provins, L. & Chanteux, H. 2-oxo-1-imidazolidinyl imidazothiadiazole derivatives. Publication number WO2019\/011767, international application number PCT\/EP2018\/068201 (2019)."},{"key":"1335_CR64","unstructured":"Quesnel, Y. 2-oxo-1-pyrrolidinyl imidazothiadiazole derivatives. Publication number WO2011\/047860, international application number PCT\/EP2010\/006434 (2011)."},{"key":"1335_CR65","unstructured":"Provins, L. Lead optimization of CYP3A4-driven metabolism: subtle structural changes, huge impact [Oral communication]. In 32nd Symposium on Medicinal Chemistry (2021)."},{"key":"1335_CR66","doi-asserted-by":"publisher","first-page":"6741","DOI":"10.1021\/acs.biochem.8b01070","volume":"57","author":"MS Rana","year":"2018","unstructured":"Rana, M. S., Wang, X. & Banerjee, A. An improved strategy for fluorescent tagging of membrane proteins for overexpression and purification in mammalian cells. Biochemistry 57, 6741\u20136751 (2018).","journal-title":"Biochemistry"},{"key":"1335_CR67","doi-asserted-by":"publisher","first-page":"2574","DOI":"10.1038\/nprot.2014.173","volume":"9","author":"A Goehring","year":"2014","unstructured":"Goehring, A. et al. Screening and large-scale expression of membrane proteins in mammalian cells for structural studies. Nat. Protoc. 9, 2574\u20132585 (2014).","journal-title":"Nat. Protoc."},{"key":"1335_CR68","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/nmeth.4169","volume":"14","author":"A Punjani","year":"2017","unstructured":"Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290\u2013296 (2017).","journal-title":"Nat. Methods"},{"key":"1335_CR69","doi-asserted-by":"publisher","first-page":"1214","DOI":"10.1038\/s41592-020-00990-8","volume":"17","author":"A Punjani","year":"2020","unstructured":"Punjani, A., Zhang, H. & Fleet, D. J. Non-uniform refinement: adaptive regularization improves single-particle cryo-EM reconstruction. Nat. Methods 17, 1214\u20131221 (2020).","journal-title":"Nat. Methods"},{"key":"1335_CR70","doi-asserted-by":"publisher","first-page":"e42166","DOI":"10.7554\/eLife.42166","volume":"7","author":"J Zivanov","year":"2018","unstructured":"Zivanov, J. et al. New tools for automated high-resolution cryo-EM structure determination in RELION-3. eLife 7, e42166 (2018).","journal-title":"eLife"},{"key":"1335_CR71","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1016\/j.jsb.2012.09.006","volume":"180","author":"SHW Scheres","year":"2012","unstructured":"Scheres, S. H. W. RELION: implementation of a Bayesian approach to cryo-EM structure determination. J. Struct. Biol. 180, 519\u2013530 (2012).","journal-title":"J. Struct. Biol."},{"key":"1335_CR72","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s42003-021-02399-1","volume":"4","author":"R Sanchez-Garcia","year":"2021","unstructured":"Sanchez-Garcia, R. et al. DeepEMhancer: a deep learning solution for cryo-EM volume post-processing. Commun. Biol. 4, 1\u20138 (2021).","journal-title":"Commun. Biol."},{"key":"1335_CR73","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","volume":"596","author":"J Jumper","year":"2021","unstructured":"Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583\u2013589 (2021).","journal-title":"Nature"},{"key":"1335_CR74","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1002\/pro.3791","volume":"29","author":"A Casa\u00f1al","year":"2020","unstructured":"Casa\u00f1al, A., Lohkamp, B. & Emsley, P. Current developments in Coot for macromolecular model building of electron cryo-microscopy and crystallographic data. Protein Sci. 29, 1069\u20131078 (2020).","journal-title":"Protein Sci."},{"key":"1335_CR75","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1107\/S0907444910007493","volume":"66","author":"P Emsley","year":"2010","unstructured":"Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486\u2013501 (2010).","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"1335_CR76","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1107\/S2059798319011471","volume":"75","author":"D Liebschner","year":"2019","unstructured":"Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr. D Struct. Biol. 75, 861\u2013877 (2019).","journal-title":"Acta Crystallogr. D Struct. Biol."},{"key":"1335_CR77","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nprot.2008.197","volume":"4","author":"L Bordoli","year":"2009","unstructured":"Bordoli, L. et al. Protein structure homology modeling using SWISS-MODEL workspace. Nat. Protoc. 4, 1\u201313 (2009).","journal-title":"Nat. Protoc."},{"key":"1335_CR78","doi-asserted-by":"publisher","first-page":"e17219","DOI":"10.7554\/eLife.17219","volume":"5","author":"RY-R Wang","year":"2016","unstructured":"Wang, R. Y.-R. et al. Automated structure refinement of macromolecular assemblies from cryo-EM maps using Rosetta. eLife 5, e17219 (2016).","journal-title":"eLife"},{"key":"1335_CR79","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1038\/nature17629","volume":"532","author":"JA Coleman","year":"2016","unstructured":"Coleman, J. A., Green, E. M. & Gouaux, E. X-ray structures and mechanism of the human serotonin transporter. Nature 532, 334\u2013339 (2016).","journal-title":"Nature"},{"key":"1335_CR80","unstructured":"Schr\u00f6dinger Release 2023-3: Maestro (Schr\u00f6dinger, LLC, New York, 2023)."},{"key":"1335_CR81","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","volume":"27","author":"GM Sastry","year":"2013","unstructured":"Sastry, G. M., Adzhigirey, M., Day, T., Annabhimoju, R. & Sherman, W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J. Comput. Aided Mol. Des. 27, 221\u2013234 (2013).","journal-title":"J. Comput. Aided Mol. Des."},{"key":"1335_CR82","doi-asserted-by":"publisher","first-page":"D370","DOI":"10.1093\/nar\/gkr703","volume":"40","author":"MA Lomize","year":"2012","unstructured":"Lomize, M. A., Pogozheva, I. D., Joo, H., Mosberg, H. I. & Lomize, A. L. OPM database and PPM web server: resources for positioning of proteins in membranes. Nucleic Acids Res. 40, D370\u2013D376 (2012).","journal-title":"Nucleic Acids Res."},{"key":"1335_CR83","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1073\/pnas.0610202104","volume":"104","author":"T Young","year":"2007","unstructured":"Young, T., Abel, R., Kim, B., Berne, B. J. & Friesner, R. A. Motifs for molecular recognition exploiting hydrophobic enclosure in protein-ligand binding. Proc. Natl Acad. Sci. USA 104, 808\u2013813 (2007).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1335_CR84","unstructured":"Desmond Molecular Dynamics System (D. E. Shaw Research, 2023)."},{"key":"1335_CR85","unstructured":"Maestro-Desmond Interoperability Tools (Schr\u00f6dinger, LLC, 2023)."},{"key":"1335_CR86","doi-asserted-by":"publisher","first-page":"4291","DOI":"10.1021\/acs.jctc.1c00302","volume":"17","author":"C Lu","year":"2021","unstructured":"Lu, C. et al. OPLS4: improving force field accuracy on challenging regimes of chemical space. J. Chem. Theory Comput. 17, 4291\u20134300 (2021).","journal-title":"J. Chem. Theory Comput."},{"key":"1335_CR87","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1021\/acsomega.6b00086","volume":"1","author":"EB Lenselink","year":"2016","unstructured":"Lenselink, E. B. et al. Predicting binding affinities for GPCR ligands using free-energy perturbation. ACS Omega 1, 293\u2013304 (2016).","journal-title":"ACS Omega"},{"key":"1335_CR88","unstructured":"Schr\u00f6dinger Release 2023-3: Glide (Schr\u00f6dinger, LLC, 2023)."},{"key":"1335_CR89","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1021\/ct300911a","volume":"9","author":"L Wang","year":"2013","unstructured":"Wang, L. et al. Modeling local structural rearrangements using FEP\/REST: application to relative binding affinity predictions of CDK2 inhibitors. J. Chem. Theory Comput. 9, 1282\u20131293 (2013).","journal-title":"J. Chem. Theory Comput."}],"updated-by":[{"DOI":"10.1038\/s41594-025-01528-2","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T00:00:00Z","timestamp":1741219200000}}],"container-title":["Nature Structural &amp; Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41594-024-01335-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41594-024-01335-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41594-024-01335-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T07:35:10Z","timestamp":1741332910000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41594-024-01335-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,19]]},"references-count":89,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["1335"],"URL":"https:\/\/doi.org\/10.1038\/s41594-024-01335-1","relation":{"correction":[{"id-type":"doi","id":"10.1038\/s41594-025-01528-2","asserted-by":"object"}]},"ISSN":["1545-9993","1545-9985"],"issn-type":[{"value":"1545-9993","type":"print"},{"value":"1545-9985","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,19]]},"assertion":[{"value":"14 November 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 May 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 June 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 March 2025","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41594-025-01528-2","URL":"https:\/\/doi.org\/10.1038\/s41594-025-01528-2","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"E.L., C.A., M.Y., L.P., A. Hall, M.P., M.L., A. Hillisch, C.W., M.G. and P.S.H. are employees of UCB Pharma. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}