Investigating Dual Modulatory Role of Mallotoxin on KCNQ1–KCNE Complexes Using Molecular Modeling

Abstract

The voltage-gated potassium ion channel KCNQ1 has physiological importance in modulation of electrical excitability in cardiac and epithelial cells. Its activity is modulated by certain proteins or small molecules and its dysfunction may result in arrhythmia, increasing risk of sudden death. Recent research has revealed that Mallotoxin (MTX), a bioactive compound derived from the plant Mallotus philippensis enhances the current generated by the KCNQ1–KCNE1 complex while exerting a modest inhibitory effect on the KCNQ1–KCNE3 channel. The molecular mechanisms underlying these contrasting effects remain unclear, given the structural similarities between the KCNE1 and KCNE3 subunits in their transmembrane regions. Therefore, we employed homology modeling to reconstruct a structural model of the KCNQ1–KCNE1 complex based on the cryo-EM structure of the KCNQ1–KCNE3 complex. Computational analyses of the electrostatic potential landscapes revealed significant differences between these complexes, with the KCNQ1–KCNE3 complex exhibiting a unique region of positive electrostatic potential located centrally within the channel, a feature absent in the KCNQ1–KCNE1 complex. Considering that MTX displays negative charge at physiological pH, we propose that MTX preferentially interacts with this positively charged domain in the KCNQ1–KCNE3 channel, leading to ion flow inhibition, which was supported by further molecular docking observation. Moreover, molecular docking studies suggest that MTX augments the activity of the KCNQ1–KCNE1 complex by stabilizing its open-state structure. These findings clarify the dual modulatory role of MTX in the KCNQ1–KCNE complex and advance therapeutic design for ion channelopathies.