The molecular basis for an allosteric inhibition of K+ -flux gating in K2P channels

ELife
Susanne RinnéNiels Decher

Abstract

Two-pore-domain potassium (K2P) channels are key regulators of many physiological and pathophysiological processes and thus emerged as promising drug targets. As for other potassium channels, there is a lack of selective blockers, since drugs preferentially bind to a conserved binding site located in the central cavity. Thus, there is a high medical need to identify novel drug-binding sites outside the conserved lipophilic central cavity and to identify new allosteric mechanisms of channel inhibition. Here, we identified a novel binding site and allosteric inhibition mechanism, disrupting the recently proposed K+-flux gating mechanism of K2P channels, which results in an unusual voltage-dependent block of leak channels belonging to the TASK subfamily. The new binding site and allosteric mechanism of inhibition provide structural and mechanistic insights into the gating of TASK channels and the basis for the drug design of a new class of potent blockers targeting specific types of K2P channels.

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Citations

Aug 21, 2019·International Journal of Molecular Sciences·David RamírezJulio Caballero
Jan 18, 2020·International Journal of Molecular Sciences·Daniel BustosWendy González
Jun 9, 2020·Frontiers in Pharmacology·Eden AraziNoam Zilberberg
Jun 6, 2020·Nature·Karin E J RödströmElisabeth P Carpenter
May 28, 2019·Chemical Biology & Drug Design·Daniel Şterbuleac
Dec 22, 2020·ELife·Aboubacar WaguePaul M Riegelhaupt
Jul 18, 2020·Annual Review of Pharmacology and Toxicology·Alistair MathiePaul D Wright
Apr 6, 2021·British Journal of Pharmacology·Aytug K KiperNiels Decher
Apr 23, 2021·Journal of Molecular Biology·Andrew M NataleDaniel L Minor
Jul 2, 2019·Journal of Medicinal Chemistry·Mauricio BedoyaDavid Ramírez

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Methods Mentioned

BETA
electrophoresis

Software Mentioned

Origin
Conformer Cluster script
HOLE
ClampFit10
Clampfit
Schrödinger
APBSmem
pClamp10
ConfGen
Adaptive Poisson - Boltzmann Solver ( APBS )

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