Structure basis for the activation of KCNQ2 by endogenous and exogenous ligands

The voltage-gated potassium channel KCNQ2 is crucial for stabilizing neuronal membrane potential, and its mutations can cause various epilepsies. KCNQ2 is activated by endogenous ligand phosphatidylinositol-4,5-bisphosphate (PIP₂) and exogenous ligands, yet the structural mechanisms underlying these activations remain unclear. Here, we report the cryo-electron microscopy structures of human KCNQ2 in complex with exogenous ligands QO-58 and QO-83 in the absence or presence of PIP₂ in either closed or open conformation. While QO-83 binds in the classical fenestration pocket of the pore domain, QO-58 mainly binds at the flank of S4 in the voltage-sensing domain. These structures, along with electrophysiological assays and computational studies, provide mechanistic insights into the ligand activation of KCNQ2 and may guide the development of anti-epileptic drugs targeting KCNQ2.