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SUMMARY:K2P channel structure\, function\, and chemical biology: Driving a
  wedge into a cryptic modulatory site  - Dan Minor\, Professor
DTSTART:20170904T130000Z
DTEND:20170904T140000Z
UID:TALK79111@talks.cam.ac.uk
CONTACT:Paula Murphy
DESCRIPTION:Polymodal thermo- and mechanosensitive two-pore domain potassi
 um (K2P) channels of the TREK subfamily generate 'leak' currents that regu
 late neuronal excitability\, respond to lipids\, temperature and mechanica
 l stretch\, and influence pain\, temperature perception and anaesthetic re
 sponses.  In contrast to other potassium channels\, K2P channels use a sel
 ectivity 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 T
 REK activators that directly stimulate the C-type gate by acting as molecu
 lar wedges. Structural studies of K2P2.1 (TREK-1) alone and with two selec
 tive activators unmask a cryptic binding pocket unlike other ion channel s
 mall-molecule binding sites. Our work defines a druggable K2P site that st
 abilizes 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 K2
 P channels.
LOCATION:Lecture Theatre\, MRC Laboratory of Molecular Biology (LMB)
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