Structural insights for the modulation of KCNQ1 channel by ML277.

Abstract

KCNQ1 is a voltage-gated potassium ion channel protein which co-assembles with its accessory regulatory KCNE subunits, KCNE1-5, in order to fulfill its diverse physiological roles in various tissues. In the heart, KCNQ1 helps maintain a normal QT interval in the electrocardiogram, and loss of function mutations can lead to long QT syndrome type 1 (LQT1), seizures, and sudden death. Activators of KCNQ1 may be a promising strategy to oppose the effect of LQT mutations. In this work, we determined the cryo-EM structure of Xenopus KCNQ1 bound to Ca2+/calmodulin with or without the KCNQ1 activator, ML277. Our results showed that a binding site for ML277 lies in the transmembrane domain of the channel which is lined by residues of the S4-S5 linker, and the S5 and S6 helices of two adjacent subunits. MD simulations, along with point mutations, support the binding site location and showed that ML277 binds almost identically in open and closed channels. Comparative structural analyses highlighted important residues for the selectivity of ML277 towards KCNQ1, among other KCNQ subfamily members, and provided an explanation for the limited efficacy of ML277 in the presence of KCNE3. This work paves the way for a better understanding of KCNQ1 regulation by small molecules and may lead to the development of novel and potent activators of KCNQ1, providing a framework for therapeutic intervention targeting KCNQ1 loss of function pathologies.