Different models of voltage-gating in Hv1 channels. (A and B) Simplified cartoon based on models of S4 movement in Hv1 channels from cryo-EM structures of the related VSP, EPR data on Hv1 (Li et al., 2014, 2015), and His accessibility (Kulleperuma et al., 2013). (A) Data by Cherny and coworkers in this issue suggest that a zinc ion (Zn) binds to V116H and D185 in the closed state at negative voltages. (B) Zinc has to unbind before outward S4 movement and channel opening at positive voltages. (C) Simplified cartoon of Hv1 channels based on the x-ray structure of the Hv1-VSP chimera (no voltage applied). The authors assumed this was a preactivated (nonconducting) state of Hv1 (Takeshita et al., 2014). (D and E) Simplified cartoon of models of S4 movement in Hv1 channels from cysteine accessibility studies (Gonzalez et al., 2010), leak currents generated in different mutants (Randolph et al., 2016), mutant cycle analysis (Berger and Isacoff, 2011; Chamberlin et al., 2014), and long MD simulations with applied transmembrane voltages (Geragotelis et al., 2020). S4 is shown in red and S1-S3 are shown in blue. Approximate locations of important residues in the different TM segments are shown, e.g., V116 in S1 as (S1)V116. Note that these cartoons are very simplified, and readers are encouraged to go to the original publications for more details about exact molecular arrangements.