Computational analysis reveals that the hERG activator RPR260243 binds at the interface between the voltage sensor and the pore, enhancing activation and slightly impairing inactivation.
Computational modeling reveals that the hERG activator RPR260243 binds at the voltage sensor-pore interface, enhancing activation and slightly impairing inactivation, providing mechanistic insights for potential LQTS2 treatments.
hERG is a voltage-gated potassium channel involved in the heart contraction whose defections are associated with the cardiac arrhythmia Long QT Syndrome type 2. The activator RPR260243 (RPR) represents a possible candidate to pharmacologically treat LQTS2 because it enhances the opening of the channel. However, the molecular detail of its action mechanism remains quite elusive. Here, we address the problem using a combination of docking, molecular dynamics simulations, and network analysis. We show that the drug preferably binds at the interface between the voltage sensor and the pore, enhancing the canonical activation path and determining a whole-structure rearrangement of the channel that slightly impairs inactivation.
Costa et al. (Fri,) conducted a other in Long QT Syndrome type 2. RPR260243 was evaluated. Computational analysis reveals that the hERG activator RPR260243 binds at the interface between the voltage sensor and the pore, enhancing activation and slightly impairing inactivation.