hERG Function in Light of Structure

The human ether-a-go-go-related gene1 (hERG) ion channel has been the subject of fascination since it was identified as a target of long QT syndrome more than 20 years ago. In this Biophysical Perspective, we look at what makes hERG intriguing and vexingly unique. By probing recent high-resolution structures in the context of functional and biochemical data, we attempt to summarize new insights into hERG-specific function and articulate important unanswered questions. X-ray crystallography and cryo-electron microscopy have revealed features not previously on the radar—the “nonswapped” transmembrane architecture, an “intrinsic ligand,” and hydrophobic pockets off a pore cavity that is surprisingly small. Advances in our understanding of drug block and inactivation mechanisms are noted, but a full picture will require more investigation.