Frontiers in Cellular Neuroscience (Mar 2015)
Molecular modeling and structural analysis of two-pore domain potassium channels TASK1 interactions with the blocker A1899
Abstract
A1899 is a potent and highly selective blocker of the Two-pore domain potassium (K2P) channel TASK-1, it acts as an antagonist blocking the K+ flux and binds to TASK-1 in the inner cavity and shows an activity in nanomolar order. This drug travels through the central cavity and finally binds in the bottom of the selectivity filter with some threonines and waters molecules forming a H-bond network and several hydrophobic interactions. Using alanine mutagenesis screens the binding site was identify involving residues in the P1 and P2 pore loops, the M2 and M4 transmembrane segments, and the halothane response element; mutations were introduced in the human TASK-1 (KCNK3, NM_002246) expressed in Oocytes from anesthetized Xenopus laevis frogs. Based in molecular modeling and structural analysis as such as molecular docking and binding free energy calculations a pose was suggested using a TASK-1 homology models. Recently, various K2P crystal structures have been obtained. We want redefined – from a structural point of view – the binding mode of A1899 in TASK-1 homology models using as a template the K2P crystal structures. By computational structural analysis we describe the molecular basis of the A1899 binding mode, how A1899 travel to its binding site and suggest an interacting pose (Figure 1.) after 100 ns of molecular dynamics simulation (MDs) we found an intra H-Bond (80% of the total MDs), a H-Bond whit Thr93 (42% of the total MDs), a pi-pi stacking interaction between a ring and Phe125 (88% of the total MDs) and several water bridges. Our experimental and computational results allow the molecular understanding of the structural binding mechanism of the selective blocker A1899 to TASK-1 channels. We identified the structural common and divergent features of TASK-1 channel through our theoretical and experimental studies of A1899 drug action.
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