Polynuclear Ruthenium Amines Inhibit K 2P Channels via a "Finger in the Dam" Mechanism.

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 _2P 2.1 (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 _2P s, inhibits RuR-sensitive K _2P s using the same mechanism. Structural knowledge enabled a generalizable design strategy for creating K _2P RuR "super-responders" having nanomolar sensitivity. Together, the data define a "finger in the dam" inhibition mechanism acting at a novel K _2P inhibitor binding site. These findings highlight the polysite nature of K _2P pharmacology and provide a new framework for K _2P inhibitor development.
Competing Interests: Declaration of Interests The other authors declare no competing interests.
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