PT - JOURNAL ARTICLE AU - Ottosson, Nina E. AU - Silverå Ejneby, Malin AU - Wu, Xiongyu AU - Yazdi, Samira AU - Konradsson, Peter AU - Lindahl, Erik AU - Elinder, Fredrik TI - A drug pocket at the lipid bilayer–potassium channel interface AID - 10.1126/sciadv.1701099 DP - 2017 Oct 01 TA - Science Advances PG - e1701099 VI - 3 IP - 10 4099 - http://advances.sciencemag.org/content/3/10/e1701099.short 4100 - http://advances.sciencemag.org/content/3/10/e1701099.full SO - Sci Adv2017 Oct 01; 3 AB - Many pharmaceutical drugs against neurological and cardiovascular disorders exert their therapeutic effects by binding to specific sites on voltage-gated ion channels of neurons or cardiomyocytes. To date, all molecules targeting known ion channel sites bind to protein pockets that are mainly surrounded by water. We describe a lipid-protein drug-binding pocket of a potassium channel. We synthesized and electrophysiologically tested 125 derivatives, analogs, and related compounds to dehydroabietic acid. Functional data in combination with docking and molecular dynamics simulations mapped a binding site for small-molecule compounds at the interface between the lipid bilayer and the transmembrane segments S3 and S4 of the voltage-sensor domain. This fundamentally new binding site for small-molecule compounds paves the way for the design of new types of drugs against diseases caused by altered excitability.