ИСТИНА

Recent research has revealed that Mallotoxin (MTX), a bioactive compound derived from the plant Mallotus philippensis, enhances current generated from 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 (PDB ID: 6V01). Computational analyses of the electrostatic potential landscapes revealed significant differences between the 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, thereby inhibiting ion flow. This hypothesis aligns with analogous findings in the KCNQ4 channel, where linopirdine, a known inhibitor, occupies a central binding site (PDB ID: 7BYN).