7XMG

Cryo-EM structure of human NaV1.7/beta1/beta2-TCN-1752

7XMG の概要

• エントリーDOI: 10.2210/pdb7xmg/pdb
• EMDBエントリー: 33296
• 分子名称: Isoform 3 of Sodium channel protein type 9 subunit alpha,Green fluorescent protein, Sodium channel subunit beta-1,Green fluorescent protein, Sodium channel subunit beta-2, ... (6 entities in total)
• 機能のキーワード: sodium channel, protein transport
• 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: 336979.25

構造登録者

Jiang, D.H.,Zhang, J.T. (登録日: 2022-04-25, 公開日: 2022-11-30, 最終更新日: 2025-07-02)

主引用文献

Zhang, J.,Shi, Y.,Huang, Z.,Li, Y.,Yang, B.,Gong, J.,Jiang, D.
Structural basis for Na V 1.7 inhibition by pore blockers.
Nat.Struct.Mol.Biol., 29:1208-1216, 2022

PubMed Abstract: Voltage-gated sodium channel Na1.7 plays essential roles in pain and odor perception. Na1.7 variants cause pain disorders. Accordingly, Na1.7 has elicited extensive attention in developing new analgesics. Here we present cryo-EM structures of human Na1.7/β1/β2 complexed with inhibitors XEN907, TC-N1752 and Na1.7-IN2, explaining specific binding sites and modulation mechanism for the pore blockers. These inhibitors bind in the central cavity blocking ion permeation, but engage different parts of the cavity wall. XEN907 directly causes α- to π-helix transition of DIV-S6 helix, which tightens the fast inactivation gate. TC-N1752 induces π-helix transition of DII-S6 helix mediated by a conserved asparagine on DIII-S6, which closes the activation gate. Na1.7-IN2 serves as a pore blocker without causing conformational change. Electrophysiological results demonstrate that XEN907 and TC-N1752 stabilize Na1.7 in inactivated state and delay the recovery from inactivation. Our results provide structural framework for Na1.7 modulation by pore blockers, and important implications for developing subtype-selective analgesics.

PubMed: 36424527
DOI: 10.1038/s41594-022-00860-1

実験手法

ELECTRON MICROSCOPY (3.09 Å)