Harnessing AlphaFold to reveal hERG channel conformational state secrets.

ABSTRACT: To design safe, selective, and effective new therapies, there must be a deep understanding of the structure and function of the drug target. One of the most difficult problems to solve has been resolution of discrete conformational states of transmembrane ion channel proteins. An example is K_V11.1 (hERG), comprising the primary cardiac repolarizing current, IKr . hERG is a notorious drug anti-target against which all promising drugs are screened to determine potential for arrhythmia. Drug interactions with the hERG inactivated state are linked to elevated arrhythmia risk, and drugs may become trapped during channel closure. While prior studies have applied AlphaFold to predict alternative protein conformations, we show that the inclusion of carefully chosen structural templates

SUBMITTER: Ngo K 

PROVIDER: S-EPMC10862728 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature