6V3C

K2P2.1(TREK-1)I110D:Ru360 bound channel structure

Summary for 6V3C

• Entry DOI: 10.2210/pdb6v3c/pdb
• Descriptor: Potassium channel subfamily K member 2, ruthenium(6+) formate azanide tetraamino(formato-kappaO)oxidoruthenate(1-) (1/1/4/1), CADMIUM ION, ... (8 entities in total)
• Functional Keywords: k channel, trek-1, mus musculus, membrane protein
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 70196.05

Authors

Pope, L.,Lolicato, M.,Minor, D.L. (deposition date: 2019-11-25, release date: 2020-02-26, Last modification date: 2024-10-23)

Primary citation

Pope, L.,Lolicato, M.,Minor Jr., D.L.
Polynuclear Ruthenium Amines Inhibit K2PChannels via a "Finger in the Dam" Mechanism.
Cell Chem Biol, 2020

PubMed Abstract: The trinuclear ruthenium amine ruthenium red (RuR) inhibits diverse ion channels, including K 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, K2.1 (TREK-1) I110D, we show that RuR acts by binding an acidic residue pair comprising the "Keystone inhibitor site" under the K CAP domain archway above the channel pore. We further establish that Ru360, a dinuclear ruthenium amine not known to affect Ks, inhibits RuR-sensitive Ks using the same mechanism. Structural knowledge enabled a generalizable design strategy for creating K RuR "super-responders" having nanomolar sensitivity. Together, the data define a "finger in the dam" inhibition mechanism acting at a novel K inhibitor binding site. These findings highlight the polysite nature of K pharmacology and provide a new framework for K inhibitor development.

PubMed: 32059793
DOI: 10.1016/j.chembiol.2020.01.011

Experimental method

X-RAY DIFFRACTION (3.51 Å)