Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277

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 Ca2+/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. KCNQ1 channels are active in heart, brain and gut. Functional loss causes epilepsy and sudden arrhythmic death. Here, authors describe a key activator drug binding site, explaining isoform and drug selectivity, and point the way for new drug design.

Automated summary

The KCNQ1 ion channel plays critical roles in various organs and its loss of function leads to severe diseases. Researchers have used cryo-EM to determine the structure of KCNQ1 bound to ML277 and identified the binding site. These findings provide insights into the mechanism of the activator and potential therapeutic interventions for KCNQ1 loss of function pathologies.