Structure of the human voltage-gated sodium channel Na _v 1.4 in complex with β1

Abstract

Voltage-gated sodium (Na) 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 channel has hampered mechanistic understanding. Here, we report the cryo-electron microscopy structure of the human Na1.4-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 channels. The structure provides a path toward mechanistic investigation of Na channels and drug discovery for Na channelopathies.

Supramolecular clustering of the cardiac sodium channel Nav1.5 in HEK293F cells, with and without the auxiliary β3‐subunit

“…By comparison with other Nav channels whose near atomic‐resolution structure has been resolved, it is likely that this epitope lie close to or underneath the central pore of the channel, albeit with some flexibility . Observed from above the membrane, a single α‐subunit is an approximate square of length ~8 nm . Thus, given the uncertainties generated by antibody size and orientation, the single 6 nm modal peak in the nearest‐neighbor distribution and the <10 nm modal peak in the cluster radii distribution for Nav1.5 α‐subunits expressed alone (Figure ) is consistent with surface‐expressed Nav 1.5 α‐subunits forming dimers, as the most common arrangement within the clusters.…”

“…32 Observed from above the membrane, a single α-subunit is an approximate square of length ~8 nm. 33 Thus, given the uncertainties generated by antibody size and orientation, the single 6 nm modal peak in the nearest-neighbor distribution and the <10 nm modal peak in the cluster radii distribution for Nav1.5 α-subunits expressed alone ( Figure 2) is consistent with surfaceexpressed Nav 1.5 α-subunits forming dimers, as the most common arrangement within the clusters. Significantly however, both the cluster radii and nearest-neighbor distributions extended considerably further than these modal values.…”

“…39 Further insights have also recently been provided from cryo-EM structures of the eel and human Nav1.4 channel α-subunits and their associations with a single β1-subunit. 33,40 Here, the transmembrane domain of the β1-subunit interacts with the S1 and S2 transmembrane helices of the DIII voltage sensor and the Ig domain forms salt-bridges with a short extracellular loop between these two helices. This α-subunit binding site on the β1 Ig domain includes a region of the N-terminus that shows sequence conservation with the trimer interface of β3.…”

Challenges and advances in atomistic simulations of potassium and sodium ion channel gating and permeation

“…) and human (Pan et al . ), have recently been determined. Their SFs display asymmetries with aspartic acid, glutamic acid, lysine and alanine (DEKA) from different channel domains forming Na + binding site Site HFS compared to the EEEE ring in prokaryotic channels.…”

Synthesis of C12‐Keto Saxitoxin Derivatives with Unusual Inhibitory Activity Against Voltage‐Gated Sodium Channels

“…Therefore, great efforts have been made to elucidatet heir structures by meanso fX -ray analysis and cryoelectron microscopy (cryo-EM), and the structures of Na V sf rom bacteria, [9] insect, [10] electric eel, [11] and mammalian [12] have been reported. Therefore, great efforts have been made to elucidatet heir structures by meanso fX -ray analysis and cryoelectron microscopy (cryo-EM), and the structures of Na V sf rom bacteria, [9] insect, [10] electric eel, [11] and mammalian [12] have been reported.…”