a molecular switch driving inactivation in the cardiac k+ channel herg分子开关驾驶心脏herg k +通道的失活.pdfVIP

A Molecular Switch Driving Inactivation in the Cardiac K+ Channel hERG ¨ 1 2 2 3 2 1 David A. Kopfer , Ulrike Hahn , Iris Ohmert , Gert Vriend , Olaf Pongs , Bert L. de Groot , Ulrich Zachariae1,3,4* ¨ 1 Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, Gottingen, Germany, 2 Center for Molecular Neurobiology, Institute for Neural Signal Transduction, University of Hamburg, Hamburg, Germany, 3 Center for Molecular and Biomolecular Informatics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands, 4 Scottish Universities Physics Alliance, School of Physics and Astronomy, The University of Edinburgh, Edinburgh, United Kingdom Abstract K+ channels control transmembrane action potentials by gating open or closed in response to external stimuli. Inactivation gating, involving a conformational change at the K+ selectivity filter, has recently been recognized as a major K+ channel regulatory mechanism. In the K+ channel hERG, inactivation controls the length of the human cardiac action potential. Mutations impairing hERG inactivation cause life-threatening cardiac arrhythmia, which also occur as undesired side effects of drugs. In this paper, we report atomistic molecular dynamics simulations, complemented by mutational and electrophysiological studies, which suggest that the selectivity filter adopts a collapsed conformation in the inactivated state of hERG. The selectivity filter is gated by an intricate hydrogen bond network around