Binding of RPR260243 at the intracellular side of the hERG1 channel pore domain slows closure of the helix bundle crossing gate

Eva-Maria Zangerl-Plessl; Wei Wu; Michael C. Sanguinetti; Anna Stary-Weinzinger

doi:10.3389/fmolb.2023.1137368

Titel

Binding of RPR260243 at the intracellular side of the hERG1 channel pore domain slows closure of the helix bundle crossing gate

Autor*in

Eva-Maria Zangerl-Plessl

Department für Pharmakologie und Toxikologie, Fakultät für Lebenswissenschaften, Universität Wien

Wei Wu

Department of Internal Medicine, Nora Eccles Harrison Cardiovascular Research & Training Institute, Division of Cardiovascular Medicine, University of Utah

Michael C. Sanguinetti

Department of Internal Medicine, Division of Cardiovascular Medicine, Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah

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Abstract

The opening and closing of voltage-dependent potassium channels is dependent on a tight coupling between movement of the voltage sensing S4 segments and the activation gate. A specific interaction between intracellular amino- and carboxyl-termini is required for the characteristically slow rate of channel closure (deactivation) of hERG1 channels. Compounds that increase hERG1 channel currents represent a novel approach for prevention of arrhythmia associated with prolonged ventricular repolarization. RPR260243 (RPR), a quinoline oxo-propyl piperidine derivative, inhibits inactivation and dramatically slows the rate of hERG1 channel deactivation. Here we report that similar to its effect on wild-type channels, RPR greatly slows the deactivation rate of hERG1 channels missing their amino-termini, or of split channels lacking a covalent link between the voltage sensor domain and the pore domain. By contrast, RPR did not slow deactivation of C-terminal truncated hERG1 channels or D540K hERG1 mutant channels activated by hyperpolarization. Together, these findings indicate that ability of RPR to slow deactivation requires an intact C-terminus, does not slow deactivation by stabilizing an interaction involving the amino-terminus or require a covalent link between the voltage sensor and pore domains. All-atom molecular dynamics simulations using the cryo-EM structure of the hERG1 channel revealed that RPR binds to a pocket located at the intracellular ends of helices S5 and S6 of a single subunit. The slowing of channel deactivation by RPR may be mediated by disruption of normal S5-S6 interactions.

Stichwort

Biochemistry, Genetics and Molecular Biology (miscellaneous)Molecular BiologyBiochemistry

Objekt-Typ

journal article

Sprache

Englisch [eng]

Persistent identifier

phaidra.univie.ac.at/o:1935645

DOI

10.3389/fmolb.2023.1137368

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