The molecular basis for an allosteric inhibition of K⁺-flux gating in K_2P channels.

ABSTRACT: Two-pore-domain potassium (K_2P) 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 K_2P channels, which results in an unusual voltage-dependent block of leak channels belonging to the TASK subfamily. The n

SUBMITTER: Rinne S 

PROVIDER: S-EPMC6391080 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature