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Side Fenestrations Provide an "anchor" for a Stable Binding of A1899 to the Pore of TASK-1 Potassium Channels

dc.contributor.authorRamírez D.
dc.contributor.authorArévalo B.
dc.contributor.authorMartínez G.
dc.contributor.authorRinné S.
dc.contributor.authorSepúlveda F.V.
dc.contributor.authorDecher N.
dc.contributor.authorGonzález W.
dc.date.accessioned2020-09-02T22:26:31Z
dc.date.available2020-09-02T22:26:31Z
dc.date.issued2017
dc.identifier10.1021/acs.molpharmaceut.7b00005
dc.identifier.citation14, 7, 2197-2208
dc.identifier.issn15438384
dc.identifier.urihttps://hdl.handle.net/20.500.12728/5946
dc.descriptionA1899 is a potent and selective inhibitor of the two-pore domain potassium (K2P) channel TASK-1. It was previously reported that A1899 acts as an open-channel blocker and binds to residues of the P1 and P2 regions, the M2 and M4 segments, and the halothane response element. The recently described crystal structures of K2P channels together with the newly identified side fenestrations indicate that residues relevant for TASK-1 inhibition are not purely facing the central cavity as initially proposed. Accordingly, the TASK-1 binding site and the mechanism of inhibition might need a re-evaluation. We have used TASK-1 homology models based on recently crystallized K2P channels and molecular dynamics simulation to demonstrate that the highly potent TASK-1 blocker A1899 requires binding to residues located in the side fenestrations. Unexpectedly, most of the previously described residues that interfere with TASK-1 blockade by A1899 project their side chains toward the fenestration lumina, underlining the relevance of these structures for drug binding in K2P channels. Despite its hydrophobicity, A1899 does not seem to use the fenestrations to gain access to the central cavity from the lipid bilayer. In contrast, binding of A1899 to residues of the side fenestrations might provide a physical "anchor", reflecting an energetically favorable binding mode that after pore occlusion stabilizes the closed state of the channels. © 2017 American Chemical Society.
dc.language.isoen
dc.publisherAmerican Chemical Society
dc.subjectA1899
dc.subjectdrug-protein interaction
dc.subjection channels
dc.subjectmolecular docking
dc.subjectmolecular dynamics
dc.subjectTASK-1
dc.subjectmonomer
dc.subjectn (2,4 difluorobenzyl) 2' [[[(4 methoxyphenyl)acetyl]amino]methyl]biphenyl 2 carboxamide
dc.subjectpotassium channel
dc.subjectpotassium channel TASK 1
dc.subjecttryptophan
dc.subjectunclassified drug
dc.subjectbenzamide derivative
dc.subjectbenzeneacetamide derivative
dc.subjectn (2,4 difluorobenzyl) 2' [[[(4 methoxyphenyl)acetyl]amino]methyl]biphenyl 2 carboxamide
dc.subjectnerve protein
dc.subjectpotassium channel subfamily K member 3
dc.subjecttandem pore domain potassium channel
dc.subjectanimal cell
dc.subjectArticle
dc.subjectcrystal structure
dc.subjectdrug binding site
dc.subjectdrug protein binding
dc.subjectfemale
dc.subjecthydrogen bond
dc.subjectlipid bilayer
dc.subjectmolecular docking
dc.subjectmolecular dynamics
dc.subjectnonhuman
dc.subjectoocyte
dc.subjectpriority journal
dc.subjectXenopus laevis
dc.subjectanimal
dc.subjectantagonists and inhibitors
dc.subjectbinding site
dc.subjectchemical phenomena
dc.subjectchemistry
dc.subjecthuman
dc.subjectmetabolism
dc.subjectmolecular dynamics
dc.subjectAnimals
dc.subjectBenzamides
dc.subjectBenzeneacetamides
dc.subjectBinding Sites
dc.subjectHumans
dc.subjectHydrophobic and Hydrophilic Interactions
dc.subjectMolecular Dynamics Simulation
dc.subjectNerve Tissue Proteins
dc.subjectPotassium Channels, Tandem Pore Domain
dc.titleSide Fenestrations Provide an "anchor" for a Stable Binding of A1899 to the Pore of TASK-1 Potassium Channels
dc.typeArticle


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