Structural Basis for the Modulation of Human KCNQ4 by Small-Molecule Drugs

Among the five KCNQ channels, also known as the K(v)7 voltage-gated potassium (K-v) channels, KCNQ2-KCNQ5 control neuronal excitability. Dysfunctions of KCNQ2-KCNQ5 are associated with neurological disorders such as epilepsy, deafness, and neuropathic pain. Here, we report the cryoelectron microscopy (cryoEM) structures of human KCNQ4 and its complexes with the opener retigabine or the blocker linopirdine at overall resolutions of 2.5, 3.1, and 3.3 angstrom, respectively. In all structures, a phosphatidylinositol 4,5-bisphosphate (PIP2) molecule inserts its head group into a cavity within each voltage-sensing domain (VSD), revealing an unobserved binding mode for PIP2. Retigabine nestles in each fenestration, inducing local shifts. Instead of staying within the central pore, linopirdine resides in a cytosolic cavity underneath the inner gate. Electrophysiological analyses of various mutants corroborated the structural observations. Our studies reveal the molecular basis for the modulatory mechanism of neuronal KCNQ channels and provide a framework for structure-facilitated drug discovery targeting these important channels.

Automated summary

This study presents the cryoEM structures of human KCNQ4 and its complexes with different drugs, revealing a unique binding mode of phosphatidylinositol 4,5-bisphosphate (PIP2) in each voltage-sensing domain (VSD) cavity. The findings provide insights into the regulatory mechanism of neuronal KCNQ channels and offer a framework for structure-assisted drug discovery targeting these important channels.