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Open and Shut Case
Voltage-sensing domains (VSDs) control the activity of voltage-gated ion channels to regulate the ion flow that underlies nerve conduction. Structural and biophysical studies have provided insight into voltage gating; however, understanding has been hindered by the lack of a crystal structure of a fully closed state. Starting from a structure of an open conducting state, a voltage-gated K+ channel, Jensen et al. (p. 229) used all-atom molecular dynamics simulations to show the conformational changes involved in switching to the closed, nonconducting state. Additional simulations revealed the major steps of channel activation. The computational determination of a closed state may guide development of drugs to treat channelopathies associated with this resting state.
Abstract
The mechanism of ion channel voltage gating—how channels open and close in response to voltage changes—has been debated since Hodgkin and Huxley’s seminal discovery that the crux of nerve conduction is ion flow across cellular membranes. Using all-atom molecular dynamics simulations, we show how a voltage-gated potassium channel (KV) switches between activated and deactivated states. On deactivation, pore hydrophobic collapse rapidly halts ion flow. Subsequent voltage-sensing domain (VSD) relaxation, including inward, 15-angstrom S4-helix motion, completes the transition. On activation, outward S4 motion tightens the VSD–pore linker, perturbing linker–S6-helix packing. Fluctuations allow water, then potassium ions, to reenter the pore; linker-S6 repacking stabilizes the open pore. We propose a mechanistic model for the sodium/potassium/calcium voltage-gated ion channel superfamily that reconciles apparently conflicting experimental data.
