7W7F

Cryo-EM structure of human NaV1.3/beta1/beta2-ICA121431

7W7F の概要

• エントリーDOI: 10.2210/pdb7w7f/pdb
• EMDBエントリー: 32343
• 分子名称: Sodium channel subunit beta-1, Sodium channel subunit beta-2, Sodium channel protein type 3 subunit alpha, ... (9 entities in total)
• 機能のキーワード: ion channel, drug, antagonist, 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: 290921.69

構造登録者

Jiang, D.,Li, X. (登録日: 2021-12-04, 公開日: 2022-04-06, 最終更新日: 2024-11-06)

主引用文献

Li, X.,Xu, F.,Xu, H.,Zhang, S.,Gao, Y.,Zhang, H.,Dong, Y.,Zheng, Y.,Yang, B.,Sun, J.,Zhang, X.C.,Zhao, Y.,Jiang, D.
Structural basis for modulation of human Na V 1.3 by clinical drug and selective antagonist.
Nat Commun, 13:1286-1286, 2022

PubMed Abstract: Voltage-gated sodium (Na) channels play fundamental roles in initiating and propagating action potentials. Na1.3 is involved in numerous physiological processes including neuronal development, hormone secretion and pain perception. Here we report structures of human Na1.3/β1/β2 in complex with clinically-used drug bulleyaconitine A and selective antagonist ICA121431. Bulleyaconitine A is located around domain I-II fenestration, providing the detailed view of the site-2 neurotoxin binding site. It partially blocks ion path and expands the pore-lining helices, elucidating how the bulleyaconitine A reduces peak amplitude but improves channel open probability. In contrast, ICA121431 preferentially binds to activated domain IV voltage-sensor, consequently strengthens the Ile-Phe-Met motif binding to its receptor site, stabilizes the channel in inactivated state, revealing an allosterically inhibitory mechanism of Na channels. Our results provide structural details of distinct small-molecular modulators binding sites, elucidate molecular mechanisms of their action on Na channels and pave a way for subtype-selective therapeutic development.

PubMed: 35277491
DOI: 10.1038/s41467-022-28808-5

実験手法

ELECTRON MICROSCOPY (3.35 Å)