Structure of human Na v 1.5 reveals the fast inactivation-related segments as a mutational hotspot for the long QT syndrome

• DOI: 10.1073/pnas.2100069118
• Publication Date: 2021-03-12T20:30:14Z
• Authors: Zhangqiang Li; Xueqin Jin; Tong Wu; Xin Zhao; Weipeng Wang; Jianlin Lei; Xiaojing Pan; Nieng Yan
• Keywords: Models, Molecular; 0301 basic medicine; Protein Conformation; Cryoelectron Microscopy; NAV1.5 Voltage-Gated Sodium Channel; 3. Good health; Long QT Syndrome; Structure-Activity Relationship; 03 medical and health sciences; Cardiac Conduction System Disease; Mutation; Humans; Ion Channel Gating; Brugada Syndrome

Significance Dysfunction of Na v 1.5, the primary cardiac channel, is associated with multiple arrhythmia syndromes, exemplified by type 3 long QT syndrome (LQT3) and Brugada (BrS). Establishment structure-function relationship mechanistic understanding disease variants will facilitate development antiarrhythmic drugs. Here we report cryo-EM structure human 1.5-E1784K, most common variant shared LQT3 BrS. Structural mapping 91 LQT3-associated mutations reveal a hotspot that involves fast inactivation segments. The high density mutation sites in this region can be reasonably interpreted “door wedge” model for inactivation, which was derived from our previous structural observations supported wealth functional characterizations.