Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Mechanisms underlying allosteric modulation of antiseizure medication binding to synaptic vesicle protein 2A (SV2A).
Journal, issue, pages	Proc Natl Acad Sci U S A, Vol. 122, Issue 36, Page e2510239122, Year 2025
Publish date	Sep 9, 2025
Authors	Anshumali Mittal / Matthew F Martin / Laurent Provins / Adrian Hall / Marie Ledecq / Christian Wolff / Michel Gillard / Peter S Horanyi / Jonathan A Coleman /
PubMed Abstract	Brivaracetam (BRV) and levetiracetam (LEV) are antiseizure medications (ASMs); UCB-J is a PET tracer targeting synaptic vesicle protein 2A (SV2A); UCB7361 is closely related to padsevonil, an ...Brivaracetam (BRV) and levetiracetam (LEV) are antiseizure medications (ASMs); UCB-J is a PET tracer targeting synaptic vesicle protein 2A (SV2A); UCB7361 is closely related to padsevonil, an experimental anticonvulsant; while UCB1244283 acts as an allosteric modulator for BRV and LEV binding but not for these other ligands. The SV2A-BRV-UCB1244283 structure reveals how UCB1244283 allosterically enhances BRV binding by occupying an allosteric site near the primary binding site, preventing BRV dissociation. This allosteric site, formed by hydrophobic and uncharged residues, is an uncharacterized small-molecule binding site in SV2A. Structural analysis and mutagenesis demonstrate that an allosteric network between the primary and allosteric sites governs high-affinity ASM binding. Our studies suggest that UCB1244283 selectively binds SV2A over SV2B and SV2C, with specific mutations disrupting binding. Structures of SV2A-UCB-J and SV2A-UCB7361 show that UCB1244283 binding is only possible when the primary site ligand does not overlap with the allosteric site, and that repositioning of Ser601, Thr605, and Leu655 is critical for allosteric ligand binding. Structural comparison of multiple SV2A complexes reveals that primary site occupancy shapes the conformation of the lumenal half of the transmembrane domain, influencing how UCB1244283 binds via a connected network that differentially stabilizes TM1 in either an open or closed conformation and repositions key allosteric and primary site residues. These insights provide a foundation for developing therapeutics targeting the allosteric site and modulating SV2A function.
External links	Proc Natl Acad Sci U S A / PubMed:40892927 / PubMed Central
Methods	EM (single particle)
Resolution	2.91 - 6.93 Å
Structure data	49758 9ntc EMDB-49758, PDB-9ntc: Structure of Synaptic Vesicle Protein 2A Bound to Brivaracetam and UCB1244283 Method: EM (single particle) / Resolution: 3.05 Å 71500 9pc9 EMDB-71500, PDB-9pc9: Structure of Synaptic Vesicle Protein 2A Bound to UCB7361 Method: EM (single particle) / Resolution: 2.91 Å 71501 9pcb EMDB-71501, PDB-9pcb: Structure of Synaptic Vesicle Protein 2A Bound to UCB-J Method: EM (single particle) / Resolution: 3.42 Å EMDB-71502: Structure of Synaptic Vesicle Protein 2A Bound to Levetiracetam and UCB1244283 Method: EM (single particle) / Resolution: 6.93 Å
Chemicals	PDB-1b1j: CRYSTAL STRUCTURE OF HUMAN ANGIOGENIN VARIANT H13A. ChemComp, No image ChemComp-VLX: Unknown entry ChemComp-CLR: CHOLESTEROL PDB-1b1i: CRYSTAL STRUCTURE OF HUMAN ANGIOGENIN PDB-1chn: MAGNESIUM BINDING TO THE BACTERIAL CHEMOTAXIS PROTEIN CHEY RESULTS IN LARGE CONFORMATIONAL CHANGES INVOLVING ITS FUNCTIONAL SURFACE PDB-1cca: THE ASP-HIS-FE TRIAD OF CYTOCHROME C PEROXIDASE CONTROLS THE REDUCTION POTENTIAL, ELECTRONIC STRUCTURE, AND COUPLING OF THE TRYPTOPHAN FREE-RADICAL TO THE HEME
Source	homo sapiens (human)
Keywords	MEMBRANE PROTEIN / Synaptic vesicle / SLC22 / Inhibitor / Positive allosteric modulator / PET tracer