title: A specific two-pore domain potassium channel blocker defines the structure of the TASK-1 open pore.
abstract: Two-pore domain potassium (K(2P)) channels play a key role in setting the membrane potential of excitable cells. Despite their role as putative targets for drugs and general anesthetics, little is known about the structure and the drug binding site of K(2P) channels. We describe A1899 as a potent and highly selective blocker of the K(2P) channel TASK-1. As A1899 acts as an open-channel blocker and binds to residues forming the wall of the central cavity, the drug was used to further our understanding of the channel pore. Using alanine mutagenesis screens, we have identified residues in both pore loops, the M2 and M4 segments, and the halothane response element to form the drug binding site of TASK-1. Our experimental data were used to validate a K(2P) open-pore homology model of TASK-1, providing structural insights for future rational design of drugs targeting K(2P) channels.
authors.affiliation: Institute for Physiology and Pathophysiology, Vegetative Physiology Group, University of Marburg, 35037 Marburg, Germany.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Streit
authors.forename: Michael F
authors.initials: MF
authors.lastname: Netter
authors.forename: Franca
authors.initials: F
authors.lastname: Kempf
authors.forename: Magdalena
authors.initials: M
authors.lastname: Walecki
authors.forename: Susanne
authors.initials: S
authors.lastname: Rinné
authors.forename: Murali K
authors.initials: MK
authors.lastname: Bollepalli
authors.forename: Regina
authors.initials: R
authors.lastname: Preisig-Müller
authors.forename: Vijay
authors.initials: V
authors.lastname: Renigunta
authors.forename: Jürgen
authors.initials: J
authors.lastname: Daut
authors.forename: Thomas
authors.initials: T
authors.lastname: Baukrowitz
authors.forename: Mark S P
authors.initials: MS
authors.lastname: Sansom
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Stansfeld
authors.forename: Niels
authors.initials: N
authors.lastname: Decher
mesh_terms: D000409:Alanine / Q000737:chemistry; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D044482:Benzeneacetamides / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D018076:DNA, Complementary / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D016296:Mutagenesis; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D009865:Oocytes / Q000166:cytology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000737:chemistry*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024683:Potassium Channels, Tandem Pore Domain / Q000737:chemistry*; D011487:Protein Conformation; D014982:Xenopus laevis
chemical_list: C558924:A 1899; D001549:Benzamides; D044482:Benzeneacetamides; D018076:DNA, Complementary; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3; D000409:Alanine; D011188:Potassium