|Recommended name:||Potassium voltage-gated channel subfamily H member 2|
|Synonyms:||ERG, ERG1, HERG, KCNH2|
|Sequence length:||1159 AA.|
The human Ether-à-go-go Related Gene (hERG) channel or KCNH2 is a voltage-gated potassium channel.
Although the 3D structure of hERG is unknown, the channel probably consists of four identical channel forming α-subunits. Each of these subunits has six transmembrane α-helices (S1-S6), S4 acts as a putative voltage-sensitive sensor. There are different binding sites for ions and larger compounds. Stary et al. (2010) published a consensus homology model of hERG in 2010, which is shown here in Jsmol (after energy minimization). With the help of this model, it was possible to dock compounds. Durdagi et al. (2012) investigated structural mechanisms of state-dependent drug binding in three different states of the channel (open, closed and open-activated).
Further information can be found reading these interesting reviews:
- Revealing the structural basis of action of hERG potassium channel activators and blockers. Perry M, Sanguinetti M, Mitcheson J, J Physiol 2010
The hERG-channel has been in the focus of pharmaceutical research as a target for years, because the inhibition of hERG potassium channels by drugs can lead to cardiac arrhythmia, a condition described as long QT syndrome. Some drugs have been withdrawn from the market or had their indications limited in many countries. The table lists some drugs, which have been withdrawn from the market or restricted for use.
|Mibefradil||Calcium channel blocker|
The International Conference of Harmonisation (ICH) set up guidelines for drug development (http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html) and all major pharmaceutical companies have adopted them. As assays are becoming faster, cheaper and more reliable, compounds are screened before getting into animal testing. To get an overview of different assays available, read these hyperlinked articles of FDA and Trends in Bio/Pharmaceutical Research:
Mechanistic insight into human ether-à-go-go-related gene (hERG) K+ channel deactivation gating from the solution structure of the EAG domain. ||The N-terminal tail of hERG contains an amphipathic α-helix that regulates channel deactivation.|