Towards a Structural View of Drug Binding to hERG K+ Channels

• Published in: Trends in pharmacological sciences (Regular ed.) Vol. 38; no. 10; pp. 899 - 907
• Main Authors: Vandenberg, Jamie I., Perozo, Eduardo, Allen, Toby W.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-10-2017
• Subjects: Arrhythmias, Cardiac - metabolism; ERG1 Potassium Channel - antagonists & inhibitors; ERG1 Potassium Channel - chemistry; ERG1 Potassium Channel - metabolism; Humans; Models, Molecular; Potassium Channel Blockers - metabolism; Potassium Channel Blockers - pharmacology; Protein Binding; Quantitative Structure-Activity Relationship
• ISSN: 0165-6147; 1873-3735
• DOI: 10.1016/j.tips.2017.06.004

The human ether-a-go-go-related gene (hERG) K+ channel is of great medical and pharmaceutical relevance. Inherited mutations in hERG result in congenital long-QT syndrome which is associated with a markedly increased risk of cardiac arrhythmia and sudden death. hERG K+ channels are also remarkably susceptible to block by a wide range of drugs, which in turn can cause drug-induced long-QT syndrome and an increased risk of sudden death. 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. It also suggests a way forward in our quest to understand why these channels are so promiscuous with respect to drug binding.
Background to hERG K+ channels and drug-induced cardiac arrhythmias.
The first near-atomic level view of the hERG K+ channel solved using single particle cryo-EM.
Insights into the structural basis of function and drug binding to hERG K+ channels.
The presence of hydrophobic pouches sprouting from the central cavity provides a plausible explanation for the promiscuity of drug binding to hERG K+ channels.