7MIX

Human N-type voltage-gated calcium channel Cav2.2 in the presence of ziconotide at 3.0 Angstrom resolution

7MIX の概要

• エントリーDOI: 10.2210/pdb7mix/pdb
• EMDBエントリー: 23867 23868
• 分子名称: Voltage-dependent N-type calcium channel subunit alpha-1B, CHOLESTEROL HEMISUCCINATE, CHOLESTEROL, ... (13 entities in total)
• 機能のキーワード: cav2.2, channels, calcium ion-selective, transport protein-toxin complex, drugs, transport protein/toxin
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 453709.62

構造登録者

Yan, N.,Gao, S.,Yao, X. (登録日: 2021-04-18, 公開日: 2021-07-07, 最終更新日: 2025-05-21)

主引用文献

Gao, S.,Yao, X.,Yan, N.
Structure of human Ca v 2.2 channel blocked by the painkiller ziconotide.
Nature, 596:143-147, 2021

PubMed Abstract: The neuronal-type (N-type) voltage-gated calcium (Ca) channels, which are designated Ca2.2, have an important role in the release of neurotransmitters. Ziconotide is a Ca2.2-specific peptide pore blocker that has been clinically used for treating intractable pain. Here we present cryo-electron microscopy structures of human Ca2.2 (comprising the core α1 and the ancillary α2δ-1 and β3 subunits) in the presence or absence of ziconotide. Ziconotide is thoroughly coordinated by helices P1 and P2, which support the selectivity filter, and the extracellular loops (ECLs) in repeats II, III and IV of α1. To accommodate ziconotide, the ECL of repeat III and α2δ-1 have to tilt upward concertedly. Three of the voltage-sensing domains (VSDs) are in a depolarized state, whereas the VSD of repeat II exhibits a down conformation that is stabilized by Ca2-unique intracellular segments and a phosphatidylinositol 4,5-bisphosphate molecule. Our studies reveal the molecular basis for Ca2.2-specific pore blocking by ziconotide and establish the framework for investigating electromechanical coupling in Ca channels.

PubMed: 34234349
DOI: 10.1038/s41586-021-03699-6

実験手法

ELECTRON MICROSCOPY (3 Å)