7WLK

CryoEM structure of human low-voltage activated T-type calcium channel Cav3.3 in complex with Otilonium Bromide(OB)

7WLK の概要

• エントリーDOI: 10.2210/pdb7wlk/pdb
• EMDBエントリー: 32586
• 分子名称: Voltage-dependent T-type calcium channel subunit alpha-1I, 2-[diethyl(methyl)-$l^{4}-azanyl]ethyl 4-[(2-octoxyphenyl)carbonylamino]benzoate, 1,2-Distearoyl-sn-glycerophosphoethanolamine, ... (6 entities in total)
• 機能のキーワード: ob, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 253788.01

構造登録者

He, L.,Yu, Z.,Dong, Y.,Chen, Q.,Zhao, Y. (登録日: 2022-01-13, 公開日: 2022-05-04, 最終更新日: 2025-06-18)

主引用文献

He, L.,Yu, Z.,Geng, Z.,Huang, Z.,Zhang, C.,Dong, Y.,Gao, Y.,Wang, Y.,Chen, Q.,Sun, L.,Ma, X.,Huang, B.,Wang, X.,Zhao, Y.
Structure, gating, and pharmacology of human Ca V 3.3 channel.
Nat Commun, 13:2084-2084, 2022

PubMed Abstract: The low-voltage activated T-type calcium channels regulate cellular excitability and oscillatory behavior of resting membrane potential which trigger many physiological events and have been implicated with many diseases. Here, we determine structures of the human T-type Ca3.3 channel, in the absence and presence of antihypertensive drug mibefradil, antispasmodic drug otilonium bromide and antipsychotic drug pimozide. Ca3.3 contains a long bended S6 helix from domain III, with a positive charged region protruding into the cytosol, which is critical for T-type Ca channel activation at low voltage. The drug-bound structures clearly illustrate how these structurally different compounds bind to the same central cavity inside the Ca3.3 channel, but are mediated by significantly distinct interactions between drugs and their surrounding residues. Phospholipid molecules penetrate into the central cavity in various extent to shape the binding pocket and play important roles in stabilizing the inhibitor. These structures elucidate mechanisms of channel gating, drug recognition, and actions, thus pointing the way to developing potent and subtype-specific drug for therapeutic treatments of related disorders.

PubMed: 35440630
DOI: 10.1038/s41467-022-29728-0

実験手法

ELECTRON MICROSCOPY (3.6 Å)