The synaptic vesicle protein 2 (SV2) family comprises highly conserved transmembrane glycoproteins with approximately 70% sequence identity across isoforms. Among these, SV2C is the most evolutionarily ancient and is preferentially expressed in dopaminergic regions of the basal ganglia. Human genetic evidence has linked SV2C to Parkinson’s disease, and prior work suggests SV2C enhances vesicular dopamine storage. SV2 proteins are also pharmacological targets: the racetam class of antiseizure medications interact with SV2s, and SV2A-selective ligands are established antiseizure therapies. Although several SV2C-selective ligands have recently been developed, the structural basis for their isoform selectivity and the mechanistic consequences for dopamine handling were not defined before this study.
The authors present cryo-electron microscopy structures for multiple conditions relevant to SV2 pharmacology: apo SV2C, SV2C bound to the high-affinity non-selective ligand padsevonil, SV2C bound to the SV2C-selective ligand UCB-F, and SV2A bound to the SV2A-selective ligand plosaracetam (also reported as ABBV-552/SDI-118). These structural datasets enabled direct comparison of ligand-binding pockets and luminal openings across isoforms and ligand states.
Comparative analysis of the resolved structures revealed a notable architectural distinction: SV2C exhibits a wider luminal opening relative to SV2A and SV2B. This difference in luminal aperture alters accessibility and geometry of the primary ligand-binding site. The wider SV2C luminal opening accommodates ligand orientations and contacts that are sterically restricted in the narrower primary binding site of SV2A and SV2B. These structural contrasts provide a plausible physical explanation for isoform-selective ligand recognition.
Structures of ligand-bound SV2 variants clarified how different compounds engage the primary binding site. In SV2C, UCB-F occupies the primary site and forms favorable interactions enabled by the broader luminal opening; those interactions are not possible in SV2A or SV2B due to the narrower pocket. Padsevonil, a high-affinity but non-selective SV2 ligand, also binds SV2C, whereas plosaracetam (SV2A-selective) binds SV2A. The structural data thus identify steric and conformational determinants that underlie ligand selectivity between SV2 isoforms. The authors emphasize that these observed binding modes and contacts can serve as a template for rational design of isoform-targeted compounds.
To connect structural selectivity with physiological function, the investigators tested ligand effects on neurotransmitter release in mouse striatal brain sections. They report that UCB-F and padsevonil reduce dopamine release in striatal slices, whereas plosaracetam does not produce this effect. These functional results correlate with the structural observation that UCB-F and padsevonil occupy SV2C binding configurations that are feasible in SV2C but not in SV2A, linking isoform-selective binding to modulation of dopamine transmission.
Biochemical experiments performed alongside the structural work support the notion that the SV2C luminal architecture and specific ligand contacts determine binding specificity. By resolving the atomic details of SV2C-ligand interactions, the study offers a structural template for designing SV2C-targeted therapeutics. Such agents could be relevant for disorders involving dopaminergic signaling, including Parkinson’s disease, and may inform novel approaches to seizures where SV2 modulation is therapeutic. The authors note that a better mechanistic understanding of SV2C structure and pharmacology could enable development of more targeted treatments for epilepsy, Parkinson’s disease, and other dopamine-related conditions.
Several coauthors (L.P., A.H., C.W., M.G., P.S.H.) are employees of UCB Pharma and hold shares in the company; other authors declared no competing interests. Reported funders include the National Institutes of Health (grants cited), the Brain & Behavior Research Foundation, SPARK-NS, and a Parkinson’s Foundation postdoctoral fellowship. The work is presented as a preprint on bioRxiv and is made available under a CC-BY-NC 4.0 International license.
This study provides cryo-EM structures that explain how SV2C accommodates certain ligands via a wider luminal opening, enabling binding modes unavailable to SV2A and SV2B. Structural and biochemical data together demonstrate that SV2C-selective binding (as with UCB-F) and non-selective binding (padsevonil) reduce striatal dopamine release, whereas an SV2A-selective ligand (plosaracetam) does not. These findings clarify molecular determinants of SV2 ligand specificity and offer a rational framework to guide development of SV2C-directed therapeutics for dopaminergic disorders and seizure conditions. Detailed experimental methods and supplementary results are provided in the preprint source.