The hERG channel (also known as KCNH2 and Kv11.1) is a
member of voltage-dependent potassium channel family and
expressed in various tissues, especially in cardiomyocytes. Similar
to other ion channels, hERG has three conformational states,
including open, close, and inactivated states. However, hERG is
activated slowly and inactivated rapidly compared with other K+
channels [95]. hERG is composed of four identicalαsubunits, and
each subunit contains sixα-helical transmembrane segments known
as S1–S6 (Fig.1). Segments S1–S4 form the voltage sensor domain
(VSD), which can sense the voltage changes of the membrane
through the positively charged residues Lys and Arg in the S4
helix [96]. Segments S5–S6 form the pore domain (i.e., the central
cavity), including the highly conserved K+channels features known
as the pore helix and the selectivity filter [96]. In addition, there are
two unique features in hERG: (a) aromatic residues Y652 and F656
in hERG instead of Ile and Val in other voltage-gated K+channels
and (b) no Pro in the S6 domain [97].
Before the crystal structure of the hERG channel was available,
a number of homology models had been primarily established
based on the solved crystal structures of some bacterial K+channels,
including KcsA (close form), KvaP (open form), and MthK (open
form). However, the sequence identity between these templates
and hERG is very low, and the widely used templates (KcsA and
MthK) only have two segments S5–S6. Therefore, most of the
homology models only contain the pore domain, which is the
position that many drugs block hERG [96, 98].
To explore the key residues of hERG interacting with blockers,
Mitcheson et al. used KcsA K+structure as a template, and estab-
lished a tetrameric channel model composed of four S6 helicesFig. 1Schematic diagram of the transmembrane topology of a hERG subunit
256 Jing Lu et al.