Cartoon representations of fast inactivation process in WT Nav channel and CW mutant. Voltage sensors in DI and DII are omitted for simplicity’s sake. Upon the onset of depolarization, VSDs from DI to DIII activate and open the channel. Later DIV VSD activates, allowing the binding of the IFM motif. The binding of the IFM motif in turn triggers a conformational change at the pore, which drives the closure of the inactivation gate at the bottom of the S6 helices. In the case of CW, however, all the conformational changes happen until the IFM motif binding. Due to the mutations, the conformational changes triggered by the IFM motif binding are impaired and subsequently in CW, the channels do not enter the fast inactivated state.