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ORIGINAL ARTICLES

Structural basis for human Cav3.2 inhibition by selective antagonists

Jian Huang^1,† , Xiao Fan^1,5,†,* , Xueqin Jin^2,† , Chen Lyu² , Qinmeng Guo² , Tao Liu² , Jiaofeng Chen² , Amaël Davakan³ , Philippe Lory³ , Nieng Yan^2,4,*

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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