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Ottosson NE, Silverå Ejneby M, Wu X, Yazdi S, Konradsson P, Lindahl E, Elinder F
Sci Adv 3 (10) e1701099 [2017-10-00; online 2017-10-25]
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.
PubMed 29075666
DOI 10.1126/sciadv.1701099
Crossref 10.1126/sciadv.1701099
pii: 1701099
pmc: PMC5656419