Isoleucine gate blocks K+ conduction in C-type inactivation
arxiv(2024)
Abstract
Many voltage-gated potassium (Kv) channels display a time-dependent
phenomenon called C-type inactivation, whereby prolonged activation by voltage
leads to the inhibition of ionic conduction, a process that involves a
conformational change at the selectivity filter toward a non-conductive state.
Recently, a high-resolution structure of a strongly inactivating triple-mutant
channel kv1.2-kv2.1-3m revealed a novel conformation of the selectivity filter
that is dilated at its outer end, distinct from the well-characterized
conductive state. While the experimental structure was interpreted as the
elusive non-conductive state, molecular dynamics simulations and
electrophysiology measurements demonstrate that the dilated filter of
kv1.2-kv2.1-3m, however, is conductive and, as such, cannot completely account
for the inactivation of the channel observed in functional experiments. An
additional conformational change implicating isoleucine residues at position
398 along the pore lining segment S6 is required to effectively block ion
conduction. It is shown that the I398 residues from the four subunits act as a
state-dependent hydrophobic gate located immediately beneath the selectivity
filter. As a critical piece of the C-type inactivation machinery, this
structural feature is the potential target of a broad class of QA blockers and
negatively charged activators thus opening new research directions towards the
development of drugs that specifically modulate gating-states of Kv channels.
MoreTranslated text
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined