Skip to content

An update on the structure of hERG

Research output: Contribution to journalArticle

Original languageEnglish
Article number1572
Number of pages13
JournalFrontiers in Pharmacology
Volume10
DOIs
DateAccepted/In press - 4 Dec 2019
DatePublished (current) - 24 Jan 2020

Abstract

The human voltage-sensitive K+ channel hERG plays a fundamental role in cardiac action potential repolarization, effectively controlling the QT interval of the electrocardiogram. Inherited loss- or gain-of-function mutations in hERG can result in dangerous “long” (LQTS) or “short” QT syndromes (SQTS), respectively, and the anomalous susceptibility of hERG to block by a diverse range of drugs underlies an acquired LQTS. A recent open channel cryo-EM structure of hERG should greatly advance understanding of the molecular basis of hERG channelopathies and drug-induced LQTS. Here we describe an update of recent research that addresses the nature of the particular gated state of hERG captured in the new structure, and the insight afforded by the structure into the molecular basis for high affinity drug block of hERG, the binding of hERG activators and the molecular basis of hERG’s peculiar gating properties. Interpretation of the pharmacology of natural SQTS mutants in the context of the structure is a promising approach to understanding the molecular basis of hERG inactivation, and the structure suggests how voltage-dependent changes in the membrane domain may be transmitted to an extracellular “turret” to effect inactivation through aromatic side chain motifs that are conserved throughout the KCNH family of channels.

    Research areas

  • hERG, cryo-EM structure, C-type inactivation, drug block, EAG, KCNH, long QT syndrome (LQTS), SQTS, channelopathy

Documents

Documents

  • Full-text PDF (final published version)

    Rights statement: This is the final published version of the article (version of record). It first appeared online via Frontiers Media at https://www.frontiersin.org/articles/10.3389/fphar.2019.01572/full . Please refer to any applicable terms of use of the publisher.

    Final published version, 1.72 MB, PDF document

    Licence: CC BY

DOI

View research connections

Related faculties, schools or groups