Structural and kinetic mechanisms of state-dependent potassium channel inhibition

: The KCNQ1 (Kv7.1) potassium ion (K+) channel plays a critical role in cardiac repolarization, while loss- or gain-of-function mutations increase the risk of life-threatening arrythmias and sudden death. Like many channels, KCNQ1 exhibits state-dependent pharmacological properties with inhibitors such as UCL2077 displaying higher potency for intermediate over activated states. Here, we report cryo-EM structures and MD simulations of KCNQ1 in complex with UCL2077 in two activation states. UCL2077 breaks tetrameric symmetry and binds in diagonally opposed protomers in pockets formed by the S5-S6 helices from one protomer and the S6 of an adjacent protomer. UCL2077 binding drives distortion of the S6 helix and causes an allosteric collapse of the pore. Specificity arises via structural configurations in the pore that occur with greater frequency in the intermediate state and are stabilized upon drug binding.