8EPL

Human R-type voltage-gated calcium channel Cav2.3 at 3.1 Angstrom resolution

8EPL の概要

• エントリーDOI: 10.2210/pdb8epl/pdb
• EMDBエントリー: 28529
• 分子名称: Voltage-dependent R-type calcium channel subunit alpha-1E, 2-acetamido-2-deoxy-beta-D-glucopyranose, Voltage-dependent L-type calcium channel subunit beta-3, ... (10 entities in total)
• 機能のキーワード: cav2.3, channels, calcium ion-selective, transport 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: 449104.96

構造登録者

Gao, S.,Yao, X.,Yan, N. (登録日: 2022-10-06, 公開日: 2022-12-14, 最終更新日: 2024-10-30)

主引用文献

Yao, X.,Wang, Y.,Wang, Z.,Fan, X.,Wu, D.,Huang, J.,Mueller, A.,Gao, S.,Hu, M.,Robinson, C.V.,Yu, Y.,Gao, S.,Yan, N.
Structures of the R-type human Ca v 2.3 channel reveal conformational crosstalk of the intracellular segments.
Nat Commun, 13:7358-7358, 2022

PubMed Abstract: The R-type voltage-gated Ca (Ca) channels Ca2.3, widely expressed in neuronal and neuroendocrine cells, represent potential drug targets for pain, seizures, epilepsy, and Parkinson's disease. Despite their physiological importance, there have lacked selective small-molecule inhibitors targeting these channels. High-resolution structures may aid rational drug design. Here, we report the cryo-EM structure of human Ca2.3 in complex with α2δ-1 and β3 subunits at an overall resolution of 3.1 Å. The structure is nearly identical to that of Ca2.2, with VSD in the down state and the other three VSDs up. A phosphatidylinositol 4,5-bisphosphate (PIP2) molecule binds to the interface of VSD and the tightly closed pore domain. We also determined the cryo-EM structure of a Ca2.3 mutant in which a Ca2-unique cytosolic helix in repeat II (designated the CH2 helix) is deleted. This mutant, named ΔCH2, still reserves a down VSD, but PIP2 is invisible and the juxtamembrane region on the cytosolic side is barely discernible. Our structural and electrophysiological characterizations of the wild type and ΔCH2 Ca2.3 show that the CH2 helix stabilizes the inactivated conformation of the channel by tightening the cytosolic juxtamembrane segments, while CH2 helix is not necessary for locking the down state of VSD.

PubMed: 36446785
DOI: 10.1038/s41467-022-35026-6

実験手法

ELECTRON MICROSCOPY (3.1 Å)