7yg5 | pdb_00007yg5
Structure of human R-type voltage-gated CaV2.3-alpha2/delta1-beta1 channel complex in the topiramate-bound state
Structural highlights
DiseaseCA2D1_HUMAN Familial short QT syndrome;Non-specific early-onset epileptic encephalopathy;Brugada syndrome. The disease is caused by variants affecting the gene represented in this entry. FunctionCA2D1_HUMAN The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel (PubMed:35293990). Plays an important role in excitation-contraction coupling (By similarity).[1] Publication Abstract from PubMedThe R-type voltage-gated calcium channel Ca(V)2.3 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 Ca(V)2.3-alpha2delta1-beta1 complex in the topiramate-bound state at a 3.0 A 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(V) and Na(V) channels, elucidating a previously unseen modulator binding site and thus pointing toward a route for the development of new drugs. Structural insights into the allosteric effects of the antiepileptic drug topiramate on the Ca(V)2.3 channel.,Gao Y, Bai Q, Zhang XC, Zhao Y Biochem Biophys Res Commun. 2024 Jun 15;725:150271. doi: , 10.1016/j.bbrc.2024.150271. PMID:38901222[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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