|Title||Structure of the human voltage-gated sodium channel Na1.4 in complex with β1.|
|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Pan, X, Li, Z, Zhou, Q, Shen, H, Wu, K, Huang, X, Chen, J, Zhang, J, Zhu, X, Lei, J, Xiong, W, Gong, H, Xiao, B, Yan, N|
|Date Published||2018 10 19|
|Keywords||Allosteric Regulation, Amino Acid Sequence, Channelopathies, Cryoelectron Microscopy, Drug Discovery, HEK293 Cells, Humans, Mutation, NAV1.4 Voltage-Gated Sodium Channel, Protein Domains, Voltage-Gated Sodium Channel beta-4 Subunit|
Voltage-gated sodium (Nav) 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 Navchannel has hampered mechanistic understanding. Here, we report the cryo-electron microscopy structure of the 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, 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 Nav channels. The structure provides a path toward mechanistic investigation of Nav channels and drug discovery for Nav channelopathies.