3 years ago

A drug pocket at the lipid bilayer-potassium channel interface

Erik Lindahl, Samira Yazdi, Nina E. Ottosson, Xiongyu Wu, Fredrik Elinder, Peter Konradsson, Malin Silverå Ejneby

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.

Publisher URL: http://advances.sciencemag.org/cgi/content/short/3/10/e1701099

DOI: 10.1126/sciadv.1701099

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