Year: 2024
Type: article
Abstract: 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.
Source: Cell Research
Institutions: Princeton University, Rockefeller University, Center for Life Sciences, State Key Laboratory of Membrane Biology, Tsinghua University, Centre National de la Recherche Scientifique, Inserm, Université de Montpellier, Institut de Génomique Fonctionnelle, Shenzhen Medical Academy of Research and Translation
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,990
Funders: Beijing Frontier Research Center for Biological Structure, Tsinghua University, Foundation for the National Institutes of Health, Princeton University, Human Frontier Science Program, Agence Nationale de la Recherche, National Natural Science Foundation of China, Tsinghua University, National Institutes of Health
OpenAlex ID: W4394726783