Cryo-EM Structure of the Open Human Ether-à-go-go-Related K+ Channel hERG

Weiwei Wang, Roderick MacKinnon

Research output: Contribution to journalArticle

131 Citations (Scopus)

Abstract

The human ether-à-go-go-related potassium channel (hERG, Kv11.1) is a voltage-dependent channel known for its role in repolarizing the cardiac action potential. hERG alteration by mutation or pharmacological inhibition produces Long QT syndrome and the lethal cardiac arrhythmia torsade de pointes. We have determined the molecular structure of hERG to 3.8 Å using cryo-electron microscopy. In this structure, the voltage sensors adopt a depolarized conformation, and the pore is open. The central cavity has an atypically small central volume surrounded by four deep hydrophobic pockets, which may explain hERG's unusual sensitivity to many drugs. A subtle structural feature of the hERG selectivity filter might correlate with its fast inactivation rate, which is key to hERG's role in cardiac action potential repolarization.

Original languageEnglish (US)
Pages (from-to)422-430.e10
JournalCell
Volume169
Issue number3
DOIs
StatePublished - Apr 20 2017
Externally publishedYes

Fingerprint

Ether
Action Potentials
Cryoelectron Microscopy
Torsades de Pointes
Long QT Syndrome
Potassium Channels
Electric potential
Molecular Structure
Molecular structure
Electron microscopy
Conformations
Cardiac Arrhythmias
Pharmacology
Mutation
Sensors
Pharmaceutical Preparations

Keywords

  • cryo-EM
  • drug-induced Long QT
  • hERG
  • hERG block
  • inactivation
  • K channel
  • structure
  • voltage-dependent gating

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Cryo-EM Structure of the Open Human Ether-à-go-go-Related K+ Channel hERG. / Wang, Weiwei; MacKinnon, Roderick.

In: Cell, Vol. 169, No. 3, 20.04.2017, p. 422-430.e10.

Research output: Contribution to journalArticle

Wang, Weiwei ; MacKinnon, Roderick. / Cryo-EM Structure of the Open Human Ether-à-go-go-Related K+ Channel hERG. In: Cell. 2017 ; Vol. 169, No. 3. pp. 422-430.e10.
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