Structure of the human voltage-gated sodium channel Na_v1.4 in complex with β1.

Abstract

Voltage-gated sodium (Na_v) channels, which are responsible for action potential generation, are implicated in many human diseases. Despite decades of rigorous characterization, the lack of a structure of any human Na_v channel has hampered mechanistic understanding. Here, we report the cryo-electron microscopy structure of the human Na_v1.4-β1 complex at 3.2-Å resolution. Accurate model building was made for the pore domain, the voltage-sensing domains, and the β1 subunit, providing insight into the molecular basis for Na⁺ permeation and kinetic asymmetry of the four repeats. Structural analysis of reported functional residues and disease mutations corroborates an allosteric blocking mechanism for fast inactivation of Na_v channels. The structure provides a path toward mechanistic investigation of Na_v channels and drug discovery for Na_v channelopathies.