Key result
Cryo-electron microscopy structures revealed that QO-83 binds in the classical fenestration pocket of the pore domain, while QO-58 binds at the flank of S4 in the voltage-sensing domain of KCNQ2.
Why the study?
The structural mechanisms underlying the activation of the voltage-gated potassium channel KCNQ2 by endogenous PIP2 and exogenous ligands remained unclear.
The study provides mechanistic insights into the ligand activation of KCNQ2, which may guide the development of anti-epileptic drugs.
Structural insights into KCNQ2 activation may guide epilepsy drug design; leaves open clinical translation pending functional studies.
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 (PIP 2 ) 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 PIP 2 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.
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Zhao et al. (2025) studied this question. QO-58 and QO-83 was evaluated on Cryo-electron microscopy structures of human KCNQ2. Cryo-electron microscopy structures revealed that QO-83 binds in the classical fenestration pocket of the pore domain, while QO-58 binds at the flank of S4 in the voltage-sensing domain of KCNQ2.
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