Structural basis of voltage gating in a partially activated K+ channel

To understand the process of voltage activation in Kv channels, we determined the cryo-EM structure of the Shaker channel ILT mutant (V369I, I372L, S376T), known to partially decouple the gating charge movement of the voltage sensing domain (VSD) and the opening of the pore domain (PD). The structure captures an intermediate state in which the VSD is only partially activated while the gate of the PD remains closed. Combined with computational modeling based on AlphaFold2 predictions and molecular dynamics simulations, we show that the VSD activation is transduced to the PD via a dynamic shift in the population equilibrium of the S4-S5 linker between two metastable positions, thereby providing the basis for electromechanical coupling between the two domains. The process by which the voltage sensor electromechanically couples to the pore in K+ channels is not fully understood. A cryo-EM structure of a partially activated state, together with computational modeling and MD simulations, clarifies the mechanistic basis for electromechanical coupling.