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TitleStructural insights into the allosteric effects of the antiepileptic drug topiramate on the Ca2.3 channel.
Journal, issue, pagesBiochem Biophys Res Commun, Vol. 725, Page 150271, Year 2024
Publish dateJun 15, 2024
AuthorsYiwei Gao / Qinru Bai / Xuejun Cai Zhang / Yan Zhao /
PubMed AbstractThe R-type voltage-gated calcium channel Ca2.3 is predominantly located in the presynapse and is implicated in distinct types of epileptic seizures. It has consequently emerged as a molecular target ...The R-type voltage-gated calcium channel Ca2.3 is predominantly located in the presynapse and is implicated in distinct types of epileptic seizures. It has consequently emerged as a molecular target in seizure treatment. Here, we determined the cryo-EM structure of the Ca2.3-α2δ1-β1 complex in the topiramate-bound state at a 3.0 Å resolution. We provide a snapshot of the binding site of topiramate, a widely prescribed antiepileptic drug, on a voltage-gated ion channel. The binding site is located at an intracellular juxtamembrane hydrophilic cavity. Further structural analysis revealed that topiramate may allosterically facilitate channel inactivation. These findings provide fundamental insights into the mechanism underlying the inhibitory effect of topiramate on Ca and Na channels, elucidating a previously unseen modulator binding site and thus pointing toward a route for the development of new drugs.
External linksBiochem Biophys Res Commun / PubMed:38901222
MethodsEM (single particle)
Resolution3.0 Å
Structure data

33808

7yg5

EMDB-33808, PDB-7yg5:
Structure of human R-type voltage-gated CaV2.3-alpha2/delta1-beta1 channel complex in the topiramate-bound state
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-R16:
HEXADECANE

ChemComp-3PE:
1,2-Distearoyl-sn-glycerophosphoethanolamine / phospholipid*YM

ChemComp-CA:
Unknown entry

ChemComp-TOR:
[(3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran-3a-yl]methyl sulfamate / medication*YM

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

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Voltage-gated calcium channel / CaV2.3 / Complex

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