---
title: "SV2C Structural Basis for Ligand Selectivity and Effects on Dopamine Release"
id: "biorxiv-16-structural-determinants-of-synaptic-vesicle-protein-2c-ligand-selectivity-and"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-16-structural-determinants-of-synaptic-vesicle-protein-2c-ligand-selectivity-and"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.10.750697v1?rss=1"
published_at: "2026-09-13T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# SV2C Structural Basis for Ligand Selectivity and Effects on Dopamine Release
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-16-structural-determinants-of-synaptic-vesicle-protein-2c-ligand-selectivity-and
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.10.750697v1?rss=1)
- **Published At:** 2026-09-13T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The synaptic vesicle protein family SV2 (SV2A, SV2B, SV2C) are transmembrane glycoproteins with ~70% sequence identity; **SV2C** is evolutionarily oldest and enriched in dopaminergic basal ganglia regions. - Genome-wide association studies have linked **SV2C** to Parkinson’s disease and SV2C is implicated in enhancing vesicular **dopamine** storage, though the underlying mechanism was previously unclear. - SV2 proteins are targets of racetam antiseizure drugs; SV2A-specific ligands are clinically used. New **SV2C-selective** ligands have been developed but their structural determinants of selectivity were unknown. - The authors report cryo-EM structures of apo **SV2C**, SV2C bound to the non-selective high-affinity ligand **padsevonil**, SV2C bound to the **SV2C-selective** ligand **UCB-F**, and **SV2A** bound to the **SV2A-selective** ligand plosaracetam (ABBV-552/SDI-118). - Structural comparisons show **SV2C** has a wider luminal opening than SV2A and SV2B; this permits **UCB-F** to bind at the primary site and make favorable interactions not possible in the narrower SV2A/SV2B primary site. - Functional assays in mouse striatal brain sections show that **UCB-F** and **padsevonil**, but not plosaracetam, reduce **dopamine release**, linking structural binding specificity to an effect on neurotransmitter release. - Biochemical experiments combined with structures provide insight into ligand specificity and present a template for rational development of therapeutics targeting **SV2C** for epilepsy, Parkinson’s disease, and other dopamine-related disorders. - Some authors are employees and shareholders of UCB Pharma; funding sources include NIH, Brain & Behavior Research Foundation, SPARK-NS, and Parkinson’s Foundation postdoctoral fellowship. Detailed experimental methods and supplementary data were provided in the preprint.
## Clinical Analysis & Structured Key Points
Structural Determinants of Synaptic Vesicle Protein 2C Ligand Selectivity and Their Impact on Dopamine Release | bioRxiv Skip to main content New Results Structural Determinants of Synaptic Vesicle Protein 2C Ligand Selectivity and Their Impact on Dopamine Release View ORCID Profile Matthew F Martin , View ORCID Profile Meghan L Bucher , View ORCID Profile Seejon Choi , View ORCID Profile Anshumali Mittal , View ORCID Profile Eugene Mosharov , View ORCID Profile Adrian Hall , View ORCID Profile Christian Wolff , View ORCID Profile Michel Gillard , View ORCID Profile Laurent Provins , View ORCID Profile Peter S Horanyi , View ORCID Profile David Sulzer , View ORCID Profile Gary W Miller , View ORCID Profile Jonathan Coleman doi: https://doi.org/10.64898/2026.09.10.750697 Matthew F Martin 1 University of Pittsburgh; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Matthew F Martin Meghan L Bucher 2 Columbia University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Meghan L Bucher Seejon Choi 2 Columbia University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Seejon Choi Anshumali Mittal 1 University of Pittsburgh; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Anshumali Mittal Eugene Mosharov 2 Columbia University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Eugene Mosharov Adrian Hall 3 UCB Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Adrian Hall Christian Wolff 3 UCB Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Christian Wolff Michel Gillard 3 UCB Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Michel Gillard Laurent Provins 3 UCB Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Laurent Provins Peter S Horanyi 3 UCB Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Peter S Horanyi David Sulzer 2 Columbia University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for David Sulzer Gary W Miller 2 Columbia University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Gary W Miller Jonathan Coleman 1 University of Pittsburgh; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jonathan Coleman For correspondence: coleman1{at}pitt.edu Abstract Info/History Metrics Supplementary material Preview PDF Abstract 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's 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's 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. Competing Interest Statement L.P., A.H., C.W., M.G., P.S.H. are employees of UCB Pharma and hold shares in UCB Pharma. The other authors declare no competing interests. Funder Information Declared National Institutes of Health, https://ror.org/01cwqze88 , R24GM154185 , R01ES023839 Brain & Behavior Research Foundation , 30153 SPARK-NS Parkinson’s Foundation Postdoctoral Research Fellowship , PF-PRF-933478 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . Back to top Previous Next Posted September 13, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Share Structural Determinants of Synaptic Vesicle Protein 2C Ligand Selectivity and Their Impact on Dopamine Release Matthew F Martin , Meghan L Bucher , Seejon Choi , Anshumali Mittal , Eugene Mosharov , Adrian Hall , Christian Wolff , Michel Gillard , Laurent Provins , Peter S Horanyi , David Sulzer , Gary W Miller , Jonathan Coleman bioRxiv 2026.09.10.750697; doi: https://doi.org/10.64898/2026.09.10.750697 Share This Article: Copy Citation Tools Structural Determinants of Synaptic Vesicle Protein 2C Ligand Selectivity and Their Impact on Dopamine Release Matthew F Martin , Meghan L Bucher , Seejon Choi , Anshumali Mittal , Eugene Mosharov , Adrian Hall , Christian Wolff , Michel Gillard , Laurent Provins , Peter S Horanyi , David Sulzer , Gary W Miller , Jonathan Coleman bioRxiv 2026.09.10.750697; doi: https://doi.org/10.64898/2026.09.10.750697 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Biochemistry Subject Areas All Articles Animal Behavior and Cognition (7983) Biochemistry (18689) Bioengineering (14808) Bioinformatics (44279) Biophysics (22531) Cancer Biology (19654) Cell Biology (26817) Clinical Trials (138) Developmental Biology (13916) Ecology (20946) Epidemiology (2067) Evolutionary Biology (25400) Genetics (16132) Genomics (23443) Immunology (18641) Microbiology (42361) Molecular Biology (17999) Neuroscience (93157) Paleontology (695) Pathology (2974) Pharmacology and Toxicology (5075) Physiology (8087) Plant Biology (15953) Scientific Communication and Education (2094) Synthetic Biology (4546) Systems Biology (10204) Zoology (2381)
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