开窗
钙通道
化学
钙
生物物理学
内生
结合位点
敌手
药理学
立体化学
医学
受体
生物化学
内科学
生物
外科
作者
Jian Huang,Xiao Fan,Xueqin Jin,Chen Lyu,Qinmeng Guo,Tao Liu,Jiaofeng Chen,Amaël Davakan,Philippe Lory,Nieng Yan
出处
期刊:Cell Research
[Springer Nature]
日期:2024-04-11
卷期号:34 (6): 440-450
被引量:24
标识
DOI:10.1038/s41422-024-00959-8
摘要
Abstract The Ca v 3.2 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 Ca v 3.2 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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