Structural basis for human Ca < sub > v < /sub > 3.2 inhibition by selective antagonists

Cell Res. 2024 Apr 11. doi: 10.1038/s41422-024-00959-8. Online ahead of print.ABSTRACTThe 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.PMID:38605177 | DOI:10.1038/s41422-024-00959-8

Source: Cell Research - April 11, 2024 Category: Cytology Authors: Jian Huang Xiao Fan Xueqin Jin Chen Lyu Qinmeng Guo Tao Liu Jiaofeng Chen Ama ël Davakan Philippe Lory Nieng Yan Source Type: research