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A drug pocket at the lipid bilayer-potassium channel interface
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
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Number of Authors: 7
2017 (English)In: Science Advances, ISSN 0036-8156, E-ISSN 2375-2548, Vol. 3, no 10, e1701099Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2017. Vol. 3, no 10, e1701099
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Other Natural Sciences
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URN: urn:nbn:se:su:diva-151005DOI: 10.1126/sciadv.1701099ISI: 000417998700021PubMedID: 29075666OAI: oai:DiVA.org:su-151005DiVA: diva2:1172804
Available from: 2018-01-10 Created: 2018-01-10 Last updated: 2018-01-10Bibliographically approved

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Lindahl, ErikElinder, Fredrik
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