Cryo-EM structures and electrophysiology revealed that ML277 binds to a specific pocket in KCNQ1, preventing channel inactivation and providing a structural basis for its activator effects.
Does ML277 modulate KCNQ1 channel currents through a specific structural binding site?
Cryo-EM structures reveal the specific binding pocket of ML277 on the KCNQ1 channel, explaining its mechanism of action in preventing inactivation and providing a basis for therapeutic targeting of KCNQ1 loss-of-function pathologies like long QT syndrome.
Abstract The KCNQ1 ion channel plays critical physiological roles in electrical excitability and K + recycling in organs including the heart, brain, and gut. Loss of function is relatively common and can cause sudden arrhythmic death, sudden infant death, epilepsy and deafness. Here, we report cryogenic electron microscopic (cryo-EM) structures of Xenopus KCNQ1 bound to Ca 2+ /Calmodulin, with and without the KCNQ1 channel activator, ML277. A single binding site for ML277 was identified, localized to a pocket lined by the S4-S5 linker, S5 and S6 helices of two separate subunits. Several pocket residues are not conserved in other KCNQ isoforms, explaining specificity. MD simulations and point mutations support this binding location for ML277 in open and closed channels and reveal that prevention of inactivation is an important component of the activator effect. Our work provides direction for therapeutic intervention targeting KCNQ1 loss of function pathologies including long QT interval syndrome and seizures.
Willegems et al. (Wed,) conducted a other in KCNQ1 channel dysfunction. ML277 vs. Unbound state (Apo) was evaluated on Structural binding site and electrophysiological modulation of KCNQ1. Cryo-EM structures and electrophysiology revealed that ML277 binds to a specific pocket in KCNQ1, preventing channel inactivation and providing a structural basis for its activator effects.