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Article Dans Une Revue Cell Research Année : 2024

Structural basis for human Cav3.2 inhibition by selective antagonists

Résumé

The Cav3.2 subtype of T-type calcium channels has been targeted for developing analgesics and anti-epileptics for its role in pain and epilepsy. Here we present the cryo-EM structures of Cav3.2 alone and in complex with four T-type calcium channel selective antagonists with overall resolutions ranging from 2.8 Å to 3.2 Å. The four compounds display two binding poses. ACT-709478 and TTA-A2 both place their cyclopropylphenyl-containing ends in the central cavity to directly obstruct ion flow, meanwhile extending their polar tails into the IV-I fenestration. TTA-P2 and ML218 project their 3,5-dichlorobenzamide groups into the II-III fenestration and place their hydrophobic tails in the cavity to impede ion permeation. The fenestration-penetrating mode immediately affords an explanation for the state-dependent activities of these antagonists. Structure-guided mutational analysis identifies several key residues that determine the T-type preference of these drugs. The structures also suggest the role of an endogenous lipid in stabilizing drug binding in the central cavity.
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Dates et versions

hal-04549967 , version 1 (17-04-2024)

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Jian Huang, Xiao Fan, Xueqin Jin, Chen Lyu, Qinmeng Guo, et al.. Structural basis for human Cav3.2 inhibition by selective antagonists. Cell Research, In press, ⟨10.1038/s41422-024-00959-8⟩. ⟨hal-04549967⟩
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