Prediction of hERG Channel Inhibition Using In Silico Techniques - Ion Channels and Their Inhibitors - page 194

a prolonged QT interval. The Long QT syndrome (LQTs) is associated with
increased risk of occurrence of potentially lethal arrhythmias called Torsade de
Pointes (TdP). The LQTs is estimated to affect 1 person every 5,000-10,000 people
[ 1 ]. The LQTs is mostly due to mutations of the hERG channel, a potassium-
selective voltage-gated channel that conducts the I Kr current, and to the KCNQ1
channel that encodes the Kv7.1 channel, which is responsible for the I Ks current. Up
to now, there are almost 300 mutations known to affect the hERG potassium
channel.
Many classes of compounds known to block the hERG potassium channel
prolong the QT interval and thus also might be involved in potentially dangerous
arrhythmias such as TdP [ 2 - 21 ].
3 Structure of the hERG Channel
The name of the hERG potassium channel origins from the human homologous
gene ether-a-go-go (eag) found in Drosophila melanogaster. The human-related
ether-a-go-go-related gene is also called KCNH2 according to the new nomencla-
ture, and the protein encoded is often referred to as hERG, even if the official
annotation according to the new nomenclature name is Kv11.1.
The hERG potassium channel has a tetrameric architecture, where each subunit
is formed by six transmembrane domains (S1-S6). Up to date two forms of hERG
are known, hERG1a and hERG1b, which can form a homo- or hetero-tetrameric
structure with different kinetic proprieties. Each subunit is formed by a voltage-
sensing transmembrane domain (S1-S4), and the K þ -selective pore (S5-S6), which
is responsible for the K þ conduction.
The K þ channel can be divided into three regions: the K þ -selectivity filter, the
central cavity and the inner pore [ 22 ]. The K þ -selectivity filter is a narrow cylinder
built to mimic perfectly an aqueous environment and to conduct specifically K þ
ions. The highly conserved signature sequence in the Kv channels (Thr/Ser-Val-
Gly-Tyr/Phe-Gly) at the C-terminal end of the selectivity filter is responsible for the
creation of the aqueous environment. The hydroxyl groups of Thr as well as the
carbonyl groups of the other four amino acids form several octahedral binding sites,
which coordinate the K þ ions analogous to a water filled environment. The diame-
ter of the cylinder is too large for the Na þ ions and thus they cannot be well
coordinated, so they stay in the aqueous environment where the water molecules
coordinate the ions.
The central cavity is a wide water-filled pore located below the selectivity filter,
whose size changes in the open and in the closed conformation.
The inner pore is located at the cytoplasmatic side of the membrane and connects
the central cavity with the cytoplasm of the cell. It consists of two concentric rings
made by four Tyr652 and four Phe656. The four Phe656 form the first ring located at
the cytoplasmatic side of the hERG channel. The four Tyr652 build the second ring,
which faces the central cavity. These two concentric rings are considered the main