Fig. 6: Conformational changes and the lock and key model for fast inactivation.

Left column is a schematic diagram of the sequence of events. The Middle column shows details of the residues involved. The Right column shows the lock and key analogy. Upon depolarization, VSD from DI to DIII activates and subsequently opens the channel. Given that DIV VSD resides in the resting state (A and E), the hydrogen bond mediated binding pocket for IFM motif is shielded (the lock is covered, I). Maintaining the depolarization, it leads to the activation DIV VSD which reorganizes the DIV S4_S5 linker and displays P1470 and N1477 towards the intracellular aqueous environment (B and F). This process is similar to opening a guard on the lock and exposing the keyhole (J). Now the DIII_DIV linker, possibly mobile in the aqueous environment, binds to the DIV S4_S5 linker positioning the IFM motif, the key, into the hydrophobic pocket (C and G), into the keyhole (K). The binding of IFM motif allows the interactions of F1291 and I1589 with the phenylalanine in IFM motif, creating a rotation of the pore-forming S6 helices in DIII and DIV (D and H), like turning the key in the keyhole (L). This helical rotation in turn locates the hydrophobic gate (yellow residues in D and H and blocking gate in L) in the permeation pathway, blocking the Na⁺ permeation as a result.