Structural Basis for Pore Blockade of the Human Cardiac Sodium Channel Na 1.5 by the Antiarrhythmic Drug Quinidine*.

TitleStructural Basis for Pore Blockade of the Human Cardiac Sodium Channel Na 1.5 by the Antiarrhythmic Drug Quinidine*.
Publication TypeJournal Article
Year of Publication2021
AuthorsLi, Z, Jin, X, Wu, T, Huang, G, Wu, K, Lei, J, Pan, X, Yan, N
JournalAngew Chem Int Ed Engl
Volume60
Issue20
Pagination11474-11480
Date Published2021 05 10
ISSN1521-3773
KeywordsAnti-Arrhythmia Agents, Cryoelectron Microscopy, Humans, Models, Molecular, NAV1.5 Voltage-Gated Sodium Channel, Quinidine
Abstract

<p>Na 1.5, the primary voltage-gated Na (Na ) channel in heart, is a major target for class I antiarrhythmic agents. Here we present the cryo-EM structure of full-length human Na 1.5 bound to quinidine, a class Ia antiarrhythmic drug, at 3.3 Å resolution. Quinidine is positioned right beneath the selectivity filter in the pore domain and coordinated by residues from repeats I, III, and IV. Pore blockade by quinidine is achieved through both direct obstruction of the ion permeation path and induced rotation of an invariant Tyr residue that tightens the intracellular gate. Structural comparison with a truncated rat Na 1.5 in the presence of flecainide, a class Ic agent, reveals distinct binding poses for the two antiarrhythmics within the pore domain. Our work reported here, along with previous studies, reveals the molecular basis for the mechanism of action of class I antiarrhythmic drugs.</p>

DOI10.1002/anie.202102196
Alternate JournalAngew Chem Int Ed Engl
PubMed ID33684260
Grant List2016YFA0500402 / / National Key R&D Program /