Institute for Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Marburg, Germany
Kirsty S Vowinkel
Institute for Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Marburg, Germany
David Ramírez
Centro de Bioinformática y Simulación Molecular, Universidad de Talca, Talca, Chile; Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
Institute of Physiology, University of Kiel, Kiel, Germany
Mauricio Bedoya
Centro de Bioinformática y Simulación Molecular, Universidad de Talca, Talca, Chile
Diana Aser
Institute for Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Marburg, Germany
Isabella Gensler
Institute for Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Marburg, Germany
Michael F Netter
Institute for Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Marburg, Germany
Phillip J Stansfeld
Structural Bioinformatics and Computational Biochemistry Unit, Department of Biochemistry, University of Oxford, Oxford, United Kingdom
Thomas Baukrowitz
Institute of Physiology, University of Kiel, Kiel, Germany
Wendy Gonzalez
Centro de Bioinformática y Simulación Molecular, Universidad de Talca, Talca, Chile; Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Universidad de Talca, Talca, Chile
Two-pore-domain potassium (K2P) channels are key regulators of many physiological and pathophysiological processes and thus emerged as promising drug targets. As for other potassium channels, there is a lack of selective blockers, since drugs preferentially bind to a conserved binding site located in the central cavity. Thus, there is a high medical need to identify novel drug-binding sites outside the conserved lipophilic central cavity and to identify new allosteric mechanisms of channel inhibition. Here, we identified a novel binding site and allosteric inhibition mechanism, disrupting the recently proposed K+-flux gating mechanism of K2P channels, which results in an unusual voltage-dependent block of leak channels belonging to the TASK subfamily. The new binding site and allosteric mechanism of inhibition provide structural and mechanistic insights into the gating of TASK channels and the basis for the drug design of a new class of potent blockers targeting specific types of K2P channels.
