Research Article

Structure of the human voltage-gated sodium channel Nav1.4 in complex with β1

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Science  06 Sep 2018:
eaau2486
DOI: 10.1126/science.aau2486

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Abstract

Voltage-gated sodium 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 Nav channel has hampered mechanistic understanding. Here we report the cryo-EM structure of human Nav1.4-β1 complex at 3.2 Å resolution. Accurate model building was made for the pore domain, the voltage-sensing domains, and the β1 subunit, giving 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 Nav channels. The structure provides a path toward mechanistic investigation of Nav channels and drug discovery for Nav channelopathies.

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