The human ether-à-go-go related gene (hERG) channel is crucial for the cardiac
action potential by contributing to the fast delayed-rectifier potassium
current. Mutations in the hERG channel result in type 2 long QT syndrome (LQT2).
The hERG channel contains a cyclic nucleotide-binding homology domain (CNBHD)
and this domain is required for the channel gating though molecular interactions
with the eag domain. Here we present solution structure of the CNBHD of the hERG
channel. The structural study reveals that the CNBHD adopts a similar fold to
other KCNH channels. It is self-liganded and it contains a short β-strand that
blocks the nucleotide-binding pocket in the β-roll. Folding of LQT2-related
mutations in this domain was shown to be affected by point mutation. Mutations
in this domain can cause protein aggregation in E. coli cells or induce
conformational changes. One mutant-R752W showed obvious chemical shift
perturbation compared with the wild-type, but it still binds to the eag domain.
The helix region from the N-terminal cap domain of the hERG channel showed
unspecific interactions with the CNBHD.
