8G1A

Cryo-EM structure of Nav1.7 with CBD

8G1A の概要

• エントリーDOI: 10.2210/pdb8g1a/pdb
• EMDBエントリー: 29665
• 分子名称: Sodium channel protein type 9 subunit alpha, 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE, 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE, ... (11 entities in total)
• 機能のキーワード: cryo-em, sodium channel, vgsc, nav1.7, cbd, 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: 292863.27

構造登録者

Fan, X.,Huang, J.,Yan, N. (登録日: 2023-02-01, 公開日: 2023-07-05, 最終更新日: 2025-05-14)

主引用文献

Huang, J.,Fan, X.,Jin, X.,Jo, S.,Zhang, H.B.,Fujita, A.,Bean, B.P.,Yan, N.
Cannabidiol inhibits Na v channels through two distinct binding sites.
Nat Commun, 14:3613-3613, 2023

PubMed Abstract: Cannabidiol (CBD), a major non-psychoactive phytocannabinoid in cannabis, is an effective treatment for some forms of epilepsy and pain. At high concentrations, CBD interacts with a huge variety of proteins, but which targets are most relevant for clinical actions is still unclear. Here we show that CBD interacts with Na1.7 channels at sub-micromolar concentrations in a state-dependent manner. Electrophysiological experiments show that CBD binds to the inactivated state of Na1.7 channels with a dissociation constant of about 50 nM. The cryo-EM structure of CBD bound to Na1.7 channels reveals two distinct binding sites. One is in the IV-I fenestration near the upper pore. The other binding site is directly next to the inactivated "wedged" position of the Ile/Phe/Met (IFM) motif on the short linker between repeats III and IV, which mediates fast inactivation. Consistent with producing a direct stabilization of the inactivated state, mutating residues in this binding site greatly reduced state-dependent binding of CBD. The identification of this binding site may enable design of compounds with improved properties compared to CBD itself.

PubMed: 37330538
DOI: 10.1038/s41467-023-39307-6

実験手法

ELECTRON MICROSCOPY (2.8 Å)