Polynuclear Ruthenium Amines Inhibit K_2P Channels via a "Finger in the Dam" Mechanism.

ABSTRACT: The trinuclear ruthenium amine ruthenium red (RuR) inhibits diverse ion channels, including K_2P potassium channels, TRPs, the calcium uniporter, CALHMs, ryanodine receptors, and Piezos. Despite this extraordinary array, there is limited information for how RuR engages targets. Here, using X-ray crystallographic and electrophysiological studies of an RuR-sensitive K_2P, K_2P2.1 (TREK-1) I110D, we show that RuR acts by binding an acidic residue pair comprising the "Keystone inhibitor site" under the K_2P CAP domain archway above the channel pore. We further establish that Ru360, a dinuclear ruthenium amine not known to affect K_2Ps, inhibits RuR-sensitive K_2Ps using the same mechanism. Structural knowledge enabled a generalizable

SUBMITTER: Pope L 

PROVIDER: S-EPMC7245552 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature