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.