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A drug pocket at the lipid bilayer-potassium channel interface
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2017 (English)In: Science Advances, ISSN 0036-8156, E-ISSN 2375-2548, Vol. 3, no 10, article id 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
AMER ASSOC ADVANCEMENT SCIENCE , 2017. Vol. 3, no 10, article id e1701099
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Biochemistry and Molecular Biology
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URN: urn:nbn:se:kth:diva-220847DOI: 10.1126/sciadv.1701099ISI: 000417998700021PubMedID: 29075666OAI: oai:DiVA.org:kth-220847DiVA, id: diva2:1172900
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QC 20180111

Available from: 2018-01-11 Created: 2018-01-11 Last updated: 2018-02-26Bibliographically approved

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Lindahl, Erik

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