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A drug pocket at the lipid bilayer-potassium channel interface
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
Stockholm University, Sweden.
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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
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-144164DOI: 10.1126/sciadv.1701099ISI: 000417998700021PubMedID: 29075666OAI: oai:DiVA.org:liu-144164DiVA, id: diva2:1171667
Note

Funding Agencies|Swedish Research Council; Swedish Brain Foundation; Swedish Heart-Lung Foundation; Swedish National Infrastructure for Computing

Available from: 2018-01-08 Created: 2018-01-08 Last updated: 2018-05-15
In thesis
1. Site and Mechanism of Action of Resin Acids on Voltage-Gated Ion Channels
Open this publication in new window or tab >>Site and Mechanism of Action of Resin Acids on Voltage-Gated Ion Channels
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Voltage-gated ion channels are pore-forming membrane proteins that open or close their gates when the voltage across the membrane is changed. They underlie the electrical activity that enables the heart to pump blood and the brain to receive and send signals. Changes in expression, distribution, and functional properties of voltage-gated ion channels can lead to diseases, such as epilepsy, cardiac arrhythmia, and pain-related disorders. Drugs that modulate the function of voltage-gated ion channels control these diseases in some patients, but the existing drugs do not adequately help all patients, and some also have severe side effects.

Resin acids are common components of pine resins, with a hydrophobic three-ringed motif and a negatively charged carboxyl group. They open big-conductance Ca2+-activated K+ (BK) channels and voltage-gated potassium (KV) channels. We aimed to characterize the binding site and mechanism of action of resin acids on a KV channel and explore the effect of a resin acid by modifying the position and valence of charge of the carboxyl group. We tested the effect on several voltage-gated ion channels, including two KV channels expressed in Xenopus laevis oocytes and several voltage-gated ion channels expressed in cardiomyocytes. For this endeavour different electrophysiological techniques, ion channels, and cell types were used together with chemical synthesis of about 140 resin-acid derivatives, mathematical models, and computer simulations.

We found that resin acids bind between the lipid bilayer and the Shaker KV channel, in the cleft between transmembrane segment S3 and S4, on the extracellular side of the voltage-sensor domain. This is a fundamentally new interaction site for small-molecule compounds that otherwise usually bind to ion channels in pockets surrounded by water. We also showed that the resin acids open the Shaker KV channel via an electrostatic mechanism, exerted on the positively charged voltage sensor S4. The effect of a resin acid increased when the negatively charged carboxyl group (the effector) and the hydrophobic three-ringed motif (anchor in lipid bilayer) were separated by three atoms: longer stalks decreased the effect. The length rule, in combination with modifications of the anchor, was used to design new resin-acid derivatives that open the human M-type (Kv7.2/7.3) channel. A naturally occurring resin acid also reduced the excitability of cardiomyocytes by affecting the voltage-dependence of several voltage-gated ion channels. The major finding was that the resin acid inactivated sodium and calcium channels, while it activated KV channels at more negative membrane voltages. Computer simulations confirmed that the combined effect on different ion channels reduced the excitability of a cardiomyocyte. Finally, the resin acid reversed induced arrhythmic firing of the cardiomyocytes.

In conclusion, resin acids are potential drug candidates for diseases such as epilepsy and cardiac arrhythmia: knowing the binding site and mechanism of action can help to fine tune the resin acid to increase the effect, as well as the selectivity.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 50
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1620
National Category
Biophysics Biochemistry and Molecular Biology Pharmaceutical Sciences Medicinal Chemistry
Identifiers
urn:nbn:se:liu:diva-147838 (URN)10.3384/diss.diva-147838 (DOI)9789176853184 (ISBN)
Public defence
2018-06-05, Hasselquistsalen, Campus US, Linköping, 13:00 (English)
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Supervisors
Available from: 2018-05-15 Created: 2018-05-15 Last updated: 2018-05-15Bibliographically approved

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Ottosson, NinaSilverå Ejneby, MalinWu, XiongyuYazdi, SamiraKonradsson, PeterElinder, Fredrik
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