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Structural modeling of hERG channel–drug interactions using Rosetta

The human ether-a-go-go-related gene (hERG) not only encodes a potassium-selective voltage-gated ion channel essential for normal electrical activity in the heart but is also a major drug anti-target. Genetic hERG mutations and blockage of the channel pore by drugs can cause long QT syndrome, which...

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Autores principales: Emigh Cortez, Aiyana M., DeMarco, Kevin R., Furutani, Kazuharu, Bekker, Slava, Sack, Jon T., Wulff, Heike, Clancy, Colleen E., Vorobyov, Igor, Yarov-Yarovoy, Vladimir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10682396/
https://www.ncbi.nlm.nih.gov/pubmed/38035013
http://dx.doi.org/10.3389/fphar.2023.1244166
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author Emigh Cortez, Aiyana M.
DeMarco, Kevin R.
Furutani, Kazuharu
Bekker, Slava
Sack, Jon T.
Wulff, Heike
Clancy, Colleen E.
Vorobyov, Igor
Yarov-Yarovoy, Vladimir
author_facet Emigh Cortez, Aiyana M.
DeMarco, Kevin R.
Furutani, Kazuharu
Bekker, Slava
Sack, Jon T.
Wulff, Heike
Clancy, Colleen E.
Vorobyov, Igor
Yarov-Yarovoy, Vladimir
author_sort Emigh Cortez, Aiyana M.
collection PubMed
description The human ether-a-go-go-related gene (hERG) not only encodes a potassium-selective voltage-gated ion channel essential for normal electrical activity in the heart but is also a major drug anti-target. Genetic hERG mutations and blockage of the channel pore by drugs can cause long QT syndrome, which predisposes individuals to potentially deadly arrhythmias. However, not all hERG-blocking drugs are proarrhythmic, and their differential affinities to discrete channel conformational states have been suggested to contribute to arrhythmogenicity. We used Rosetta electron density refinement and homology modeling to build structural models of open-state hERG channel wild-type and mutant variants (Y652A, F656A, and Y652A/F656 A) and a closed-state wild-type channel based on cryo-electron microscopy structures of hERG and EAG1 channels. These models were used as protein targets for molecular docking of charged and neutral forms of amiodarone, nifekalant, dofetilide, d/l-sotalol, flecainide, and moxifloxacin. We selected these drugs based on their different arrhythmogenic potentials and abilities to facilitate hERG current. Our docking studies and clustering provided atomistic structural insights into state-dependent drug–channel interactions that play a key role in differentiating safe and harmful hERG blockers and can explain hERG channel facilitation through drug interactions with its open-state hydrophobic pockets.
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spelling pubmed-106823962023-11-30 Structural modeling of hERG channel–drug interactions using Rosetta Emigh Cortez, Aiyana M. DeMarco, Kevin R. Furutani, Kazuharu Bekker, Slava Sack, Jon T. Wulff, Heike Clancy, Colleen E. Vorobyov, Igor Yarov-Yarovoy, Vladimir Front Pharmacol Pharmacology The human ether-a-go-go-related gene (hERG) not only encodes a potassium-selective voltage-gated ion channel essential for normal electrical activity in the heart but is also a major drug anti-target. Genetic hERG mutations and blockage of the channel pore by drugs can cause long QT syndrome, which predisposes individuals to potentially deadly arrhythmias. However, not all hERG-blocking drugs are proarrhythmic, and their differential affinities to discrete channel conformational states have been suggested to contribute to arrhythmogenicity. We used Rosetta electron density refinement and homology modeling to build structural models of open-state hERG channel wild-type and mutant variants (Y652A, F656A, and Y652A/F656 A) and a closed-state wild-type channel based on cryo-electron microscopy structures of hERG and EAG1 channels. These models were used as protein targets for molecular docking of charged and neutral forms of amiodarone, nifekalant, dofetilide, d/l-sotalol, flecainide, and moxifloxacin. We selected these drugs based on their different arrhythmogenic potentials and abilities to facilitate hERG current. Our docking studies and clustering provided atomistic structural insights into state-dependent drug–channel interactions that play a key role in differentiating safe and harmful hERG blockers and can explain hERG channel facilitation through drug interactions with its open-state hydrophobic pockets. Frontiers Media S.A. 2023-11-14 /pmc/articles/PMC10682396/ /pubmed/38035013 http://dx.doi.org/10.3389/fphar.2023.1244166 Text en Copyright © 2023 Emigh Cortez, DeMarco, Furutani, Bekker, Sack, Wulff, Clancy, Vorobyov and Yarov-Yarovoy. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Emigh Cortez, Aiyana M.
DeMarco, Kevin R.
Furutani, Kazuharu
Bekker, Slava
Sack, Jon T.
Wulff, Heike
Clancy, Colleen E.
Vorobyov, Igor
Yarov-Yarovoy, Vladimir
Structural modeling of hERG channel–drug interactions using Rosetta
title Structural modeling of hERG channel–drug interactions using Rosetta
title_full Structural modeling of hERG channel–drug interactions using Rosetta
title_fullStr Structural modeling of hERG channel–drug interactions using Rosetta
title_full_unstemmed Structural modeling of hERG channel–drug interactions using Rosetta
title_short Structural modeling of hERG channel–drug interactions using Rosetta
title_sort structural modeling of herg channel–drug interactions using rosetta
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10682396/
https://www.ncbi.nlm.nih.gov/pubmed/38035013
http://dx.doi.org/10.3389/fphar.2023.1244166
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