9AYL の概要
| エントリーDOI | 10.2210/pdb9ayl/pdb |
| EMDBエントリー | 43995 |
| 分子名称 | Voltage-dependent T-type calcium channel subunit alpha-1H, N-{1-[(5-cyanopyridin-2-yl)methyl]-1H-pyrazol-3-yl}-2-{4-[1-(trifluoromethyl)cyclopropyl]phenyl}acetamide, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total) |
| 機能のキーワード | cav3.2, voltage gated calcium channel, cryo-em, transport protein, act-709478 |
| 由来する生物種 | Homo sapiens (human) 詳細 |
| タンパク質・核酸の鎖数 | 1 |
| 化学式量合計 | 240874.75 |
| 構造登録者 | |
| 主引用文献 | Huang, J.,Fan, X.,Jin, X.,Lyu, C.,Guo, Q.,Liu, T.,Chen, J.,Davakan, A.,Lory, P.,Yan, N. Structural basis for human Ca v 3.2 inhibition by selective antagonists. Cell Res., 34:440-450, 2024 Cited by PubMed Abstract: The Ca3.2 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 Ca3.2 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. PubMed: 38605177DOI: 10.1038/s41422-024-00959-8 主引用文献が同じPDBエントリー |
| 実験手法 | ELECTRON MICROSCOPY (2.8 Å) |
構造検証レポート
検証レポート(詳細版)
をダウンロード
をダウンロード
