An Update on the Structure of hERG

Area of Science:

• Cardiovascular Physiology
• Molecular Biology
• Structural Biology

Background:

• The human ether-à-go-go-related gene (hERG) potassium channel is crucial for cardiac action potential repolarization and QT interval regulation.
• Mutations and drug interactions affecting hERG function can lead to life-threatening long QT syndrome (LQTS) and short QT syndrome (SQTS).

Purpose of the Study:

• To analyze a recent open channel cryo-electron microscopy (cryo-EM) structure of hERG.
• To elucidate the molecular basis of hERG channelopathies and drug-induced LQTS.
• To understand the gating properties, drug binding, and inactivation mechanisms of hERG.

Main Methods:

• Analysis of a recent open channel cryo-electron microscopy (cryo-EM) structure of hERG.
• Interpretation of structure-function relationships for hERG mutants and drug interactions.
• Comparative analysis of conserved motifs within the KCNH family of channels.

Main Results:

• The cryo-EM structure provides insights into the specific gated state of hERG.
• The structure explains high-affinity drug block and the binding of hERG activators.
• Structural interpretation of short QT syndrome (SQTS) mutants offers understanding of hERG inactivation.

Conclusions:

• The hERG structure is a valuable tool for understanding channelopathies and drug effects.
• The structure reveals mechanisms underlying hERG's unique gating and inactivation.
• Conserved aromatic motifs are implicated in voltage-dependent inactivation transmission.