8HMB

Cryo-EM structure of human high-voltage activated L-type calcium channel CaV1.2 in complex with benidipine (BEN)

これはPDB形式変換不可エントリーです。

8HMB の概要

• エントリーDOI: 10.2210/pdb8hmb/pdb
• EMDBエントリー: 34892
• 分子名称: Isoform 2c of Voltage-dependent L-type calcium channel subunit beta-2, Voltage-dependent L-type calcium channel subunit alpha, Voltage-dependent calcium channel subunit alpha-2/delta-1, ... (8 entities in total)
• 機能のキーワード: ben bound state, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 442508.22

構造登録者

Wei, Y.,Yu, Z.,Zhao, Y. (登録日: 2022-12-02, 公開日: 2024-04-24, 最終更新日: 2026-04-15)

主引用文献

Wei, Y.,Yu, Z.,Wang, L.,Li, X.,Li, N.,Bai, Q.,Wang, Y.,Li, R.,Meng, Y.,Xu, H.,Wang, X.,Dong, Y.,Huang, Z.,Zhang, X.C.,Zhao, Y.
Structural bases of inhibitory mechanism of Ca V 1.2 channel inhibitors.
Nat Commun, 15:2772-2772, 2024

PubMed Abstract: The voltage-gated calcium channel Ca1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of Ca1.2 are involved in brain and heart diseases. Pharmacological inhibition of Ca1.2 is therefore of therapeutic value. Here, we report cryo-EM structures of Ca1.2 in the absence or presence of the antirheumatic drug tetrandrine or antihypertensive drug benidipine. Tetrandrine acts as a pore blocker in a pocket composed of S6, S6, and S6 helices and forms extensive hydrophobic interactions with Ca1.2. Our structure elucidates that benidipine is located in the D-D fenestration site. Its hydrophobic sidechain, phenylpiperidine, is positioned at the exterior of the pore domain and cradled within a hydrophobic pocket formed by S5, S6, and S6 helices, providing additional interactions to exert inhibitory effects on both L-type and T-type voltage gated calcium channels. These findings provide the structural foundation for the rational design and optimization of therapeutic inhibitors of voltage-gated calcium channels.

PubMed: 38555290
DOI: 10.1038/s41467-024-47116-8

実験手法

ELECTRON MICROSCOPY (3.3 Å)