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ORIGINAL ARTICLES

Structural basis for human Cav3.2 inhibition by selective antagonists

Jian Huang1,† , Xiao Fan1,5,†,* , Xueqin Jin2,† , Chen Lyu2 , Qinmeng Guo2 , Tao Liu2 , Jiaofeng Chen2 , Amaël Davakan3 , Philippe Lory3 , Nieng Yan2,4,*

1Department of Molecular Biology, Princeton University, Princeton, NJ, USA
2Beijing Frontier Research Center for Biological Structures, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
3IGF, Université de Montpellier, CNRS, INSERM, LabEx ‘Ion Channel Science and Therapeutics’, Montpellier, France
4Institute of Bio-Architecture and Bio-Interactions, Shenzhen Medical Academy of Research and Translation, Shenzhen, Guangdong, China
5Present address: Laboratory of Neurophysiology and Behavior, The Rockefeller University, New York, NY, USA
These authors contributed equally: Jian Huang, Xiao Fan, Xueqin Jin
* Correspondence: Xiao Fan(fanxiao0606@gmail.com)Nieng Yan(nyan@tsinghua.edu.cn)

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.

https://doi.org/10.1038/s41422-024-00959-8

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