Key result
A1899 acts as an open-channel blocker of TASK-1, binding to residues in the pore loops and M2/M4 segments, which validated an open-pore homology model of the channel.
The structural characterization of the TASK-1 open pore and its binding site for A1899 provides a foundation for rational drug design targeting K(2P) channels.
Preclinical findings only; leaves open whether open-pore TASK-1 blockade can guide selective K(2P) therapeutics in humans.
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.
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Streit et al. (2011) studied this question. A1899 was evaluated on Identification of drug binding site and validation of K(2P) open-pore homology model of TASK-1. A1899 acts as an open-channel blocker of TASK-1, binding to residues in the pore loops and M2/M4 segments, which validated an open-pore homology model of the channel.
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