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TitleStructures of synaptic vesicle protein 2A and 2B bound to anticonvulsants.
Journal, issue, pagesNat Struct Mol Biol, Year 2024
Publish dateJun 19, 2024
AuthorsAnshumali Mittal / Matthew F Martin / Elena J Levin / Christopher Adams / Meng Yang / Laurent Provins / Adrian Hall / Martin Procter / Marie Ledecq / Alexander Hillisch / Christian Wolff / Michel Gillard / Peter S Horanyi / Jonathan A Coleman /
PubMed AbstractEpilepsy is a common neurological disorder characterized by abnormal activity of neuronal networks, leading to seizures. The racetam class of anti-seizure medications bind specifically to a membrane ...Epilepsy is a common neurological disorder characterized by abnormal activity of neuronal networks, leading to seizures. The racetam class of anti-seizure medications bind specifically to a membrane protein found in the synaptic vesicles of neurons called synaptic vesicle protein 2 (SV2) A (SV2A). SV2A belongs to an orphan subfamily of the solute carrier 22 organic ion transporter family that also includes SV2B and SV2C. The molecular basis for how anti-seizure medications act on SV2s remains unknown. Here we report cryo-electron microscopy structures of SV2A and SV2B captured in a luminal-occluded conformation complexed with anticonvulsant ligands. The conformation bound by anticonvulsants resembles an inhibited transporter with closed luminal and intracellular gates. Anticonvulsants bind to a highly conserved central site in SV2s. These structures provide blueprints for future drug design and will facilitate future investigations into the biological function of SV2s.
External linksNat Struct Mol Biol / PubMed:38898101
MethodsEM (single particle)
Resolution3.2 - 3.8 Å
Structure data

42430

8uo8

EMDB-42430, PDB-8uo8:
Structure of synaptic vesicle protein 2B with padsevonil
Method: EM (single particle) / Resolution: 3.2 Å

42431

8uo9

EMDB-42431, PDB-8uo9:
Structure of synaptic vesicle protein 2A in complex with a nanobody
Method: EM (single particle) / Resolution: 3.3 Å

42432

8uoa

EMDB-42432, PDB-8uoa:
Structure of the synaptic vesicle protein 2A Luminal domain in complex with a nanobody
Method: EM (single particle) / Resolution: 3.8 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose


ChemComp, No image

ChemComp-X3U:
Unknown entry

ChemComp-PS1:
1,2-DIDECANOYL-SN-GLYCERO-3-[PHOSPHO-L-SERINE]

ChemComp-9Z9:
(3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en / detergent*YM

ChemComp-43Y:
[(2R)-3-[oxidanyl-[2-(trimethyl-$l^{4}-azanyl)ethoxy]phosphoryl]oxy-2-propanoyloxy-propyl] propanoate

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-HOH:
WATER


ChemComp, No image

ChemComp-X49:
Unknown entry

Source
  • homo sapiens (human)
  • lama glama (llama)
KeywordsTRANSPORT PROTEIN / Synaptic vesicle / SLC22 / Inhibitor / Antiepileptic / Nanobody / AEDs

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