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

• Published in: Cell Vol. 169; no. 3; pp. 422 - 430.e10
• Main Authors: Wang, Weiwei, MacKinnon, Roderick
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.04.2017
• Subjects: Amino Acid Sequence; cryo-EM; Cryoelectron Microscopy; drug-induced Long QT; ERG1 Potassium Channel - chemistry; ERG1 Potassium Channel - isolation & purification; ERG1 Potassium Channel - metabolism; ERG1 Potassium Channel - ultrastructure; hERG; hERG block; Humans; inactivation; K+ channel; Models, Molecular; Protein Conformation; Sequence Alignment; structure; voltage-dependent gating; K+ channel; drug-induced Long QT; hERG; voltage-dependent gating; inactivation; hERG block; cryo-EM; structure; K(+) channel
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2017.03.048

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. [Display omitted] •hERG channel structure is determined at 3.8 Å using single-particle cryo-EM•hERG channel is open with the voltage sensors in a depolarized conformation•Unique properties of the central cavity likely contribute to hERG block by many drugs•A subtle rearrangement in hERG’s selectivity filter correlates with rapid inactivation Structural analysis of the hERG channel helps to understand known human channelopathy mutations and why the channel is extremely sensitive to a wide range of drugs.