{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:22Z","timestamp":1792790362994,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,13]]},"group-title":"Biochemistry","reference-count":79,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["R24GM154185"],"award-info":[{"award-number":["R24GM154185"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01ES023839"],"award-info":[{"award-number":["R01ES023839"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Brain & Behavior Research Foundation","award":["30153"],"award-info":[{"award-number":["30153"]}],"id":[{"id":"https:\/\/ror.org\/03a63f080","id-type":"ROR","asserted-by":"crossref"}]},{"name":"SPARK-NS"},{"name":"Parkinson\u2019s Foundation Postdoctoral Research Fellowship","award":["PF-PRF-933478"],"award-info":[{"award-number":["PF-PRF-933478"]}],"id":[{"id":"https:\/\/ror.org\/05mx85j86","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The synaptic vesicle protein 2 (SV2) family is a highly conserved group of transmembrane glycoproteins sharing approximately 70% sequence identity. SV2A and SV2B are broadly distributed throughout the brain, while SV2C, the evolutionarily oldest member of the family, is primarily found in dopaminergic brain regions in the basal ganglia. Genome-wide association studies have linked SV2C to Parkinson\u2019s disease, and SV2C appears to enhance dopamine storage in synaptic vesicles, but the basis for this effect is unknown. SV2s are the target of the racetam class of antiseizure medications, and SV2A-specific ligands are widely used to treat seizures. Recently several SV2C-specific ligands have been developed, but the structural basis for ligand specificity is unclear. A better understanding of SV2C structure, function, and pharmacology could lead to better targeted therapies for epilepsy, Parkinson\u2019s disease, and other dopamine-related conditions. Here we present cryo-EM structures of apo SV2C, SV2C bound to the high affinity non-selective SV2 ligand padsevonil, SV2C bound to the SV2C-selective ligand UCB-F, and SV2A bound to the SV2A-selective ligand plosaracetam (also known as ABBV-552\/SDI-118). We find that SV2C has a wider luminal opening than SV2A and SV2B, which allows for UCB-F to bind to the primary site and form favorable interactions that are not possible in the narrower primary binding site of SV2A and SV2B. We also demonstrate that UCB-F and padsevonil, but not plosaracetam, reduce dopamine release in striatal sections of mouse brain. Our biochemical experiments and structures provide insights into SV2 ligand specificity and offer a template for the rational development of therapeutics targeting SV2C.<\/jats:p>","DOI":"10.64898\/2026.09.10.750697","type":"posted-content","created":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T14:10:14Z","timestamp":1789308614000},"source":"Crossref","is-referenced-by-count":0,"title":["Structural Determinants of Synaptic Vesicle Protein 2C Ligand Selectivity and Their Impact on Dopamine Release"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4298-1604","authenticated-orcid":false,"given":"Matthew F.","family":"Martin","sequence":"first","affiliation":[{"name":"Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7613-3836","authenticated-orcid":false,"given":"Meghan L.","family":"Bucher","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8229-1704","authenticated-orcid":false,"given":"Sejoon","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0478-2682","authenticated-orcid":false,"given":"Anshumali","family":"Mittal","sequence":"additional","affiliation":[{"name":"Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0229-7114","authenticated-orcid":false,"given":"Eugene","family":"Mosharov","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7869-6835","authenticated-orcid":false,"given":"Adrian","family":"Hall","sequence":"additional","affiliation":[{"name":"UCB, Braine-l\u2019Alleud, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0210-8608","authenticated-orcid":false,"given":"Christian","family":"Wolff","sequence":"additional","affiliation":[{"name":"UCB, Braine-l\u2019Alleud, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0403-2328","authenticated-orcid":false,"given":"Michel","family":"Gillard","sequence":"additional","affiliation":[{"name":"UCB, Braine-l\u2019Alleud, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4352-7086","authenticated-orcid":false,"given":"Laurent","family":"Provins","sequence":"additional","affiliation":[{"name":"UCB, Braine-l\u2019Alleud, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2218-9986","authenticated-orcid":false,"given":"Peter S.","family":"Horanyi","sequence":"additional","affiliation":[{"name":"UCB, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7632-0439","authenticated-orcid":false,"given":"David","family":"Sulzer","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8984-1284","authenticated-orcid":false,"given":"Gary W.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0001-6195","authenticated-orcid":false,"given":"Jonathan A.","family":"Coleman","sequence":"additional","affiliation":[{"name":"Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091711400871000_2026.09.10.750697v1.1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.14-09-05223.1994"},{"key":"2026091711400871000_2026.09.10.750697v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(93)90024-W"},{"key":"2026091711400871000_2026.09.10.750697v1.3","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.100.4.1284"},{"key":"2026091711400871000_2026.09.10.750697v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2010.09.063"},{"key":"2026091711400871000_2026.09.10.750697v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2017.12.029"},{"key":"2026091711400871000_2026.09.10.750697v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(99)00370-X"},{"key":"2026091711400871000_2026.09.10.750697v1.7","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjad054"},{"key":"2026091711400871000_2026.09.10.750697v1.8","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-14-87"},{"key":"2026091711400871000_2026.09.10.750697v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2019.02.003"},{"key":"2026091711400871000_2026.09.10.750697v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90319-8"},{"key":"2026091711400871000_2026.09.10.750697v1.11","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2017.00148"},{"key":"2026091711400871000_2026.09.10.750697v1.12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.6.2150"},{"key":"2026091711400871000_2026.09.10.750697v1.13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.26.15268"},{"key":"2026091711400871000_2026.09.10.750697v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2015.02.011"},{"key":"2026091711400871000_2026.09.10.750697v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.clineuro.2019.03.020"},{"key":"2026091711400871000_2026.09.10.750697v1.16","doi-asserted-by":"crossref","first-page":"100425","DOI":"10.1016\/j.ebr.2020.100425","article-title":"A de novo heterozygous rare variant in SV2A causes epilepsy and levetiracetam-induced drug-resistant status epilepticus","volume":"15","year":"2021","journal-title":"Epilepsy & Behavior Reports"},{"key":"2026091711400871000_2026.09.10.750697v1.17","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C114.584516"},{"key":"2026091711400871000_2026.09.10.750697v1.18","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M800738200"},{"key":"2026091711400871000_2026.09.10.750697v1.19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1501627112"},{"key":"2026091711400871000_2026.09.10.750697v1.20","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M000674200"},{"key":"2026091711400871000_2026.09.10.750697v1.21","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M407502200"},{"key":"2026091711400871000_2026.09.10.750697v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2004.12.011"},{"key":"2026091711400871000_2026.09.10.750697v1.23","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4248-14.2015"},{"key":"2026091711400871000_2026.09.10.750697v1.24","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4781-09.2010"},{"key":"2026091711400871000_2026.09.10.750697v1.25","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00259.2010"},{"key":"2026091711400871000_2026.09.10.750697v1.26","doi-asserted-by":"publisher","DOI":"10.1126\/science.1123654"},{"key":"2026091711400871000_2026.09.10.750697v1.27","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E08-07-0765"},{"key":"2026091711400871000_2026.09.10.750697v1.28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1001207"},{"key":"2026091711400871000_2026.09.10.750697v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/srep43588"},{"key":"2026091711400871000_2026.09.10.750697v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-56304-z"},{"key":"2026091711400871000_2026.09.10.750697v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-37860-8"},{"key":"2026091711400871000_2026.09.10.750697v1.32","doi-asserted-by":"crossref","first-page":"fcaa183","DOI":"10.1093\/braincomms\/fcaa183","article-title":"Padsevonil randomized Phase IIa trial in treatment-resistant focal epilepsy: a translational approach","volume":"2","year":"2020","journal-title":"Brain Commun"},{"key":"2026091711400871000_2026.09.10.750697v1.33","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1002\/epi4.12656","article-title":"Efficacy and safety of adjunctive padsevonil in adults with drug-resistant focal epilepsy: Results from two double-blind, randomized, placebo-controlled trials","volume":"7","year":"2022","journal-title":"Epilepsia Open"},{"key":"2026091711400871000_2026.09.10.750697v1.34","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.119.261149"},{"key":"2026091711400871000_2026.09.10.750697v1.35","doi-asserted-by":"publisher","DOI":"10.1517\/17460441.2.11.1537"},{"key":"2026091711400871000_2026.09.10.750697v1.36","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308208101"},{"key":"2026091711400871000_2026.09.10.750697v1.37","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13340"},{"key":"2026091711400871000_2026.09.10.750697v1.38","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13638"},{"key":"2026091711400871000_2026.09.10.750697v1.39","doi-asserted-by":"publisher","DOI":"10.1111\/epi.14532"},{"key":"2026091711400871000_2026.09.10.750697v1.40","doi-asserted-by":"crossref","first-page":"e70994","DOI":"10.1002\/alz.70994","article-title":"ABBV-552 in patients with mild Alzheimer\u2019s disease: a randomized phase IIb trial","volume":"21","year":"2025","journal-title":"Alzheimers Dement"},{"key":"2026091711400871000_2026.09.10.750697v1.41","doi-asserted-by":"crossref","first-page":"1066447","DOI":"10.3389\/fphar.2022.1066447","article-title":"SDI-118, a novel procognitive SV2A modulator: First-in-human randomized controlled trial including PET\/fMRI assessment of target engagement","volume":"13","year":"2023","journal-title":"Front Pharmacol"},{"key":"2026091711400871000_2026.09.10.750697v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-024-01335-1"},{"key":"2026091711400871000_2026.09.10.750697v1.43","doi-asserted-by":"crossref","first-page":"e2510239122","DOI":"10.1073\/pnas.2510239122","article-title":"Mechanisms underlying allosteric modulation of antiseizure medication binding to synaptic vesicle protein 2A (SV2A)","volume":"122","year":"2025","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"2026091711400871000_2026.09.10.750697v1.44","doi-asserted-by":"crossref","first-page":"10748","DOI":"10.1038\/s41467-025-65781-1","article-title":"Structural pharmacology of SV2A reveals an allosteric modulation mechanism in the major facilitator superfamily","volume":"16","year":"2025","journal-title":"Nat Commun"},{"key":"2026091711400871000_2026.09.10.750697v1.45","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-47322-4"},{"key":"2026091711400871000_2026.09.10.750697v1.46","doi-asserted-by":"crossref","first-page":"4172","DOI":"10.1038\/s41467-025-59545-0","article-title":"Structures of native SV2A reveal the binding mode for tetanus neurotoxin and anti-epileptic racetams","volume":"16","year":"2025","journal-title":"Nat Commun"},{"key":"2026091711400871000_2026.09.10.750697v1.47","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.16311"},{"key":"2026091711400871000_2026.09.10.750697v1.48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1616892114"},{"key":"2026091711400871000_2026.09.10.750697v1.49","doi-asserted-by":"crossref","first-page":"1437144","DOI":"10.3389\/fncel.2024.1437144","article-title":"Synaptic Vesicle Glycoprotein 2C: a role in Parkinson\u2019s disease","volume":"18","year":"2024","journal-title":"Front Cell Neurosci"},{"key":"2026091711400871000_2026.09.10.750697v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.01.033"},{"key":"2026091711400871000_2026.09.10.750697v1.51","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.schres.2013.07.008","article-title":"Genotypic variation in the SV2C gene impacts response to atypical antipsychotics the CATIE study","volume":"149","year":"2013","journal-title":"Schizophr Res"},{"key":"2026091711400871000_2026.09.10.750697v1.52","doi-asserted-by":"publisher","DOI":"10.2217\/pgs.15.183"},{"key":"2026091711400871000_2026.09.10.750697v1.53","doi-asserted-by":"crossref","unstructured":"Reden\u0161ek, S. et al. Dopaminergic Pathway Genes Influence Adverse Events Related to Dopaminergic Treatment in Parkinson\u2019s Disease. Front. Pharmacol. 10, (2019).","DOI":"10.3389\/fphar.2019.00008"},{"key":"2026091711400871000_2026.09.10.750697v1.54","doi-asserted-by":"publisher","DOI":"10.1038\/tpj.2012.38"},{"key":"2026091711400871000_2026.09.10.750697v1.55","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10277"},{"key":"2026091711400871000_2026.09.10.750697v1.56","doi-asserted-by":"publisher","DOI":"10.1002\/mds.29283"},{"key":"2026091711400871000_2026.09.10.750697v1.57","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.4c00029"},{"key":"2026091711400871000_2026.09.10.750697v1.58","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s41181-019-0080-5","article-title":"Improved synthesis of SV2A targeting radiotracer [11C]UCB-J","volume":"4","year":"2019","journal-title":"EJNMMI Radiopharmacy and Chemistry"},{"key":"2026091711400871000_2026.09.10.750697v1.59","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.115.168179"},{"key":"2026091711400871000_2026.09.10.750697v1.60","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.1111\/ejn.16311","article-title":"Synaptic vesicle glycoprotein 2C enhances vesicular storage of dopamine and counters dopaminergic toxicity","volume":"59","year":"2024","journal-title":"Eur J of Neuroscience"},{"key":"2026091711400871000_2026.09.10.750697v1.61","doi-asserted-by":"publisher","DOI":"10.1021\/cb400259n"},{"key":"2026091711400871000_2026.09.10.750697v1.62","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2015.01.022"},{"key":"2026091711400871000_2026.09.10.750697v1.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2012.04.010"},{"key":"2026091711400871000_2026.09.10.750697v1.64","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15363-0"},{"key":"2026091711400871000_2026.09.10.750697v1.65","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0210-20.2020"},{"key":"2026091711400871000_2026.09.10.750697v1.66","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.0c00983"},{"key":"2026091711400871000_2026.09.10.750697v1.67","doi-asserted-by":"publisher","DOI":"10.64898\/2026.03.19.711868"},{"key":"2026091711400871000_2026.09.10.750697v1.68","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-200303030-00035"},{"key":"2026091711400871000_2026.09.10.750697v1.69","doi-asserted-by":"publisher","DOI":"10.1016\/S1059131102001930"},{"key":"2026091711400871000_2026.09.10.750697v1.70","doi-asserted-by":"publisher","DOI":"10.1006\/phrs.2000.0689"},{"key":"2026091711400871000_2026.09.10.750697v1.71","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-200307010-00017"},{"key":"2026091711400871000_2026.09.10.750697v1.72","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2009.09.024"},{"key":"2026091711400871000_2026.09.10.750697v1.73","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1121081109"},{"key":"2026091711400871000_2026.09.10.750697v1.74","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2009.07.004"},{"key":"2026091711400871000_2026.09.10.750697v1.75","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1021\/acs.chemrestox.0c00380","article-title":"Assessing Vesicular Monoamine Transport and Toxicity Using Fluorescent False Neurotransmitters","volume":"34","year":"2021","journal-title":"Chem. Res. Toxicol"},{"key":"2026091711400871000_2026.09.10.750697v1.76","doi-asserted-by":"publisher","DOI":"10.1101\/2025.09.08.674935"},{"key":"2026091711400871000_2026.09.10.750697v1.77","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.17219"},{"key":"2026091711400871000_2026.09.10.750697v1.78","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1107\/S2059798318002425","article-title":"ISOLDE: a physically realistic environment for model building into low-resolution electron-density maps","volume":"74","year":"2018","journal-title":"Acta Crystallogr D Struct Biol"},{"key":"2026091711400871000_2026.09.10.750697v1.79","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.10.750697","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T18:40:23Z","timestamp":1789670423000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.09.10.750697"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,13]]},"references-count":79,"URL":"https:\/\/doi.org\/10.64898\/2026.09.10.750697","relation":{},"subject":[],"published":{"date-parts":[[2026,9,13]]},"subtype":"preprint"}}