Abstract

The KCNQ1 potassium channel, co-assembled with KCNE regulatory subunits, is critical for cardiac and epithelial function, and its dysfunction is linked to severe channelopathies. This study investigates the **dual modulatory role of Mallotoxin** on the KCNQ1–KCNE complexes, a mechanism not fully understood at the molecular level. Using advanced **molecular modeling** techniques, including molecular docking and dynamics simulations, we aimed to elucidate the binding sites and conformational changes induced by Mallotoxin on the KCNQ1/KCNE1 and KCNQ1/KCNE3 complexes. Our findings reveal that Mallotoxin exhibits distinct binding modes in the two complexes, suggesting a **concentration-dependent dual effect**: an inhibitory action at a high-affinity site and a facilitatory action at a separate, lower-affinity site. Specifically, the inhibitory binding site was identified near the pore region, while the facilitatory site was located at the voltage-sensing domain interface. These results provide a crucial **structural basis** for the complex pharmacology of KCNQ1 channels and offer new insights for the rational design of selective KCNQ1 modulators with therapeutic potential.