Dan Roden
Faculty Member
Last active: 3/24/2020

An allosteric mechanism for drug block of the human cardiac potassium channel KCNQ1.

Yang T, Smith JA, Leake BF, Sanders CR, Meiler J, Roden DM
Mol Pharmacol. 2013 83 (2): 481-9

PMID: 23193163 · PMCID: PMC3558809 · DOI:10.1124/mol.112.081513

The intracellular aspect of the sixth transmembrane segment within the ion-permeating pore is a common binding site for many voltage-gated ion channel blockers. However, the exact site(s) at which drugs bind remain controversial. We used extensive site-directed mutagenesis coupled with molecular modeling to examine mechanisms in drug block of the human cardiac potassium channel KCNQ1. A total of 48 amino acid residues in the S6 segment, S4-S5 linker, and the proximal C-terminus of the KCNQ1 channel were mutated individually to alanine; alanines were mutated to cysteines. Residues modulating drug block were identified when mutant channels displayed <50% block on exposure to drug concentrations that inhibited wild-type current by ≥90%. Homology modeling of the KCNQ1 channel based on the Kv1.2 structure unexpectedly predicted that the key residue modulating drug block (F351) faces away from the permeating pore. In the open-state channel model, F351 lines a pocket that also includes residues L251 and V254 in S4-S5 linker. Docking calculations indicated that this pocket is large enough to accommodate quinidine. To test this hypothesis, L251A and V254A mutants were generated that display a reduced sensitivity to blockage with quinidine. Thus, our data support a model in which open state block of this channel occurs not via binding to a site directly in the pore but rather by a novel allosteric mechanism: drug access to a side pocket generated in the open-state channel configuration and lined by S6 and S4-S5 residues.

MeSH Terms (15)

Alanine Allosteric Regulation Animals Binding Sites Cell Line CHO Cells Cricetinae Cysteine Heart Humans KCNQ1 Potassium Channel Models, Molecular Mutagenesis, Site-Directed Myocardium Quinidine

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