The conformational shifts of the voltage sensing domains between NavRh and NavAb

Bacterial Voltage-Gated Sodium Channels (BacNaVs) from the Soil, Sea, and Salt Lakes Enlighten Molecular Mechanisms of Electrical Signaling and Pharmacology in the Brain and Heart

“…Uniquely, the Na V Rh structure presents four simultaneous views of its VSD because one channel tetramer crystallized within the asymmetric unit 39; 146 , providing a fortuitous example of the potential structural dynamics that are possible within a VSD. Structural plasticity is seen within the S3-S4 linkers of two subunits (Fig.…”

“…6b). Na V Rh achieves R4 transfer above the CTC through the concerted intracellular movements of its S1-S3 segments 146 , where its CTC appears “downshifted” within the membrane compared to Na V Ab (Fig. 6b).…”

“…This difference is reminiscent of the observed VSD disengagement from the PD upon channel closure in simulations of Kv1.2/2.1 chimera in lipid membranes 160 and would seem to be in line with the independent character of the VSDs with respect to the overall protein structure 28; 129; 131; 142; 161 . Such displacements raise interesting questions about the exact functional states of the full length BacNa V structures, how there can be strong coupling between the internal motions of S4 within the VSD in response to voltage, and whether such global VSD motions have a role in voltage sensing 146 . Furthermore, upon comparing the available Na V Ab I217C and WT structures, significant movements of the VSDs around the PD are also seen that may highlight a novel isoform selective receptor site that is potentially druggable in the eukaryotic Na V channels.…”

A complicated complex: Ion channels, voltage sensing, cell membranes and peptide inhibitors

“…Third, the glycerol backbone is a stereoisomer of that in phosphatides ( Figs 5A and 6) -providing a different chirality [84] [85], most likely by binding to the down state of these channels (it contains 6 of the 7 conserved residues in the HwTx-IV family of peptides as shown in Table 4). This would suggest that the up state of the VSD of KvAP in a POPE/POPG mix shares structural homology to the down state of Na V channels and the mechanism of voltage gating of K V channels in archea may indeed be rather different to that observed in mammalian cells considering the divergent lipid composition of the lipid bilayer as well as the significant structural changes involving loop sizes and the helix break in KvAP [86].…”

Molecular Architecture of a Sodium Channel S6 Helix

“…Within this particular region, the activation gate residues (Tyr 405 of DI, Phe 960 of DII, Phe 1449 of DIII, and Phe 1752 of DIV) of Na V 1.7 align reasonably well with those of Na V Rh (Leu 219 ), although it is clear that when the helices extend toward the extracellular direction, they begin to separate. Given that Na V Rh and Na V Ab are different bacterial sodium channels, it is understandable that notable differences exist between Na V Rh and Na V Ab (35) and between our Na V 1.7 structural model and Na V Rh or Na V Ab. Nevertheless, within the activation gate region, the structural elements are relatively conserved; therefore, it is not surprising that our modeling provided guidance for our mutagenesis and voltage clamp experiments, which permitted us to dissect the architecture of an S6 helix.…”