K2P channel structure, function, and chemical biology: Driving a wedge into a cryptic modulatory site

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• Dan Minor, Professor
• Monday 04 September 2017, 14:00-15:00
• Lecture Theatre, MRC Laboratory of Molecular Biology (LMB).

If you have a question about this talk, please contact Paula Murphy.

Polymodal thermo- and mechanosensitive two-pore domain potassium (K2P) channels of the TREK subfamily generate ‘leak’ currents that regulate neuronal excitability, respond to lipids, temperature and mechanical stretch, and influence pain, temperature perception and anaesthetic responses. In contrast to other potassium channels, K2P channels use a selectivity filter ‘C-type’ gate as the principal gating site. K2P channels stuffer from a poor pharmacological profiles that has limited mechanistic and biological studies. We recently discovered a class of small-molecule TREK activators that directly stimulate the C-type gate by acting as molecular wedges. Structural studies of K2P2 .1 (TREK-1) alone and with two selective activators unmask a cryptic binding pocket unlike other ion channel small-molecule binding sites. Our work defines a druggable K2P site that stabilizes the C-type gate ‘leak mode’ and provides direct evidence for K2P selectivity filter gating. Our studies define a new means for ion channel control and offer a new direction for developing a chemical biology for K2P channels.

This talk is part of the Neurobiology series.

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• Lecture Theatre, MRC Laboratory of Molecular Biology (LMB)
• Neurobiology

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