Structural basis for human Ca_(v)3.2 inhibition by selective antagonists  

作　　者：Jian Huang Xiao Fan Xueqin Jin Chen Lyu Qinmeng Guo Tao Liu Jiaofeng Chen Amaël Davakan Philippe Lory Nieng Yan 

机构地区：[1]Department of Molecular Biology,Princeton University,Princeton,NJ,USA [2]Beijing 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 [3]IGF,Universitéde Montpellier,CNRS,INSERM,LabEx‘Ion Channel Science and Therapeutics’,Montpellier,France [4]Institute of Bio-Architecture and Bio-Interactions,Shenzhen Medical Academy of Research and Translation,Shenzhen,Guangdong,China [5]Laboratory of Neurophysiology and Behavior,The Rockefeller University,New York,NY,USA

出　　处：《Cell Research》2024年第6期440-450,共11页细胞研究（英文版）

摘　　要：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 2.8Åto 3.2Å.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.

关 键 词：CAVITY EPILEPSY PERMEATION 

分 类 号：Q2[生物学—细胞生物学]