7DTC

voltage-gated sodium channel Nav1.5-E1784K

7DTC の概要

• エントリーDOI: 10.2210/pdb7dtc/pdb
• EMDBエントリー: 30850
• 分子名称: Sodium channel protein type 5 subunit alpha, 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total)
• 機能のキーワード: voltage-gated sodium channel, membrane protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 233734.87

構造登録者

Yan, N.,Pan, X.,Li, Z. (登録日: 2021-01-04, 公開日: 2021-03-24, 最終更新日: 2025-06-25)

主引用文献

Li, Z.,Jin, X.,Wu, T.,Zhao, X.,Wang, W.,Lei, J.,Pan, X.,Yan, N.
Structure of human Na v 1.5 reveals the fast inactivation-related segments as a mutational hotspot for the long QT syndrome.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Na1.5 is the primary voltage-gated Na (Na) channel in the heart. Mutations of Na1.5 are associated with various cardiac disorders exemplified by the type 3 long QT syndrome (LQT3) and Brugada syndrome (BrS). E1784K is a common mutation that has been found in both LQT3 and BrS patients. Here we present the cryo-EM structure of the human Na1.5-E1784K variant at an overall resolution of 3.3 Å. The structure is nearly identical to that of the wild-type human Na1.5 bound to quinidine. Structural mapping of 91- and 178-point mutations that are respectively associated with LQT3 and BrS reveals a unique distribution pattern for LQT3 mutations. Whereas the BrS mutations spread evenly on the structure, LQT3 mutations are clustered mainly to the segments in repeats III and IV that are involved in gating, voltage-sensing, and particularly inactivation. A mutational hotspot involving the fast inactivation segments is identified and can be mechanistically interpreted by our "door wedge" model for fast inactivation. The structural analysis presented here, with a focus on the impact of mutations on inactivation and late sodium current, establishes a structure-function relationship for the mechanistic understanding of Na1.5 channelopathies.

PubMed: 33712541
DOI: 10.1073/pnas.2100069118

実験手法

ELECTRON MICROSCOPY (3.3 Å)