Structure of human Na_v1.5 reveals the fast inactivation-related segments as a mutational hotspot for the long QT syndrome.

ABSTRACT: Na_v1.5 is the primary voltage-gated Na⁺ (Na_v) channel in the heart. Mutations of Na_v1.5 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 Na_v1.5-E1784K variant at an overall resolution of 3.3 Å. The structure is nearly identical to that of the wild-type human Na_v1.5 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 cluster

SUBMITTER: Li Z 

PROVIDER: S-EPMC7980460 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature