Towards a Structural View of Drug Binding to hERG K+ Channels.
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TLDR
The recent determination of the near-atomic resolution structure of the hERG K+ channel, using single-particle cryo-electron microscopy (cryo-EM), provides tremendous insights into how these channels work and suggests a way forward in the quest to understand why these channels are so promiscuous with respect to drug binding.About:
This article is published in Trends in Pharmacological Sciences.The article was published on 2017-10-01 and is currently open access. It has received 49 citations till now. The article focuses on the topics: hERG & Sudden death.read more
Citations
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Journal ArticleDOI
Antibodies and venom peptides: new modalities for ion channels.
TL;DR: Strategies to selectively modulate ion channel function using biologics — namely, antibodies and venom-derived peptides — are discussed, highlighting opportunities, hurdles and future directions for the field.
Journal ArticleDOI
A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels.
Marcus Schewe,Han Sun,Ümit Mert,Alexandra Mackenzie,Alexandra Mackenzie,Ashley C. W. Pike,Friederike Schulz,Cristina E. Constantin,Kirsty S Vowinkel,Linus J. Conrad,Aytug K. Kiper,Wendy González,Marianne Musinszki,Marie Tegtmeier,David C. Pryde,Belabed Hassane,Marc Nazaré,Bert L. de Groot,Niels Decher,Bernd Fakler,Elisabeth P. Carpenter,Elisabeth P. Carpenter,Stephen J. Tucker,Thomas Baukrowitz +23 more
TL;DR: An unrecognized polypharmacology among K+ channel activators is uncovered and a filter gating machinery that is conserved across different families of K+ channels with implications for rational drug design is highlighted.
Journal ArticleDOI
Atomistic Simulations of Membrane Ion Channel Conduction, Gating, and Modulation
TL;DR: Modern simulations offer a range of molecular-level insights into ion channel function and modulation as a learning platform for mechanistic discovery and drug development.
Journal ArticleDOI
A current understanding of drug-induced QT prolongation and its implications for anticancer therapy.
TL;DR: This finding supports a role for inhibition of this enzyme, either directly or by inhibition of upstream kinases, to prolong QT through mechanisms that are being worked out, but include enhanced inward 'late' sodium current during the plateau of the action potential.
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Revealing Molecular Determinants of hERG Blocker and Activator Binding
TL;DR: A hERG conformational state allowing discrimination of blockers vs non-blockers from docking is identified and the binding pocket agrees with mutagenesis data and blocker binding modes fit the hERG blocker pharmacophore.
References
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A mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel
TL;DR: The finding that HERG encodes IKr channels provides a mechanistic link between certain forms of inherited and acquired LQT, and that an additional subunit may be required for drug sensitivity.
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Drug-induced prolongation of the QT interval.
TL;DR: The single most common cause of the withdrawal or restriction of the use of marketed drugs has been QT-interval prolongation associated with polymorphic ventricular tachycardia, or torsade de pointes, a condition that can be fatal.
Differential Sensitivity to Block by Class III Antiarrhythmic Agents
TL;DR: An envelope of tails test was used to show that the delayed rectifier K § current (Iv.) of guinea pig ventricular myocytes results from the activation of two outward K § currents as mentioned in this paper.
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Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents.
TL;DR: The magnitude of IKr was small relative to fully activated IKs, and the two currents were of similar magnitude when measured during a relatively short pulse protocol at membrane potentials typical of the plateau phase of cardiac action potentials.
Journal ArticleDOI
HERG, a Human Inward Rectifier in the Voltage-Gated Potassium Channel Family
TL;DR: The properties of HERG channels are consistent with the gating properties of Eag-related and other outwardly rectifying, S4-containing potassium channels, but with the addition of an inactivation mechanism that attenuates potassium efflux during depolarization.
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