TY - JOUR
T1 - Structural Basis for Pore Blockade of the Human Cardiac Sodium Channel Nav1.5 by the Antiarrhythmic Drug Quinidine**
AU - Li, Zhangqiang
AU - Jin, Xueqin
AU - Wu, Tong
AU - Huang, Gaoxingyu
AU - Wu, Kun
AU - Lei, Jianlin
AU - Pan, Xiaojing
AU - Yan, Nieng
N1 - Publisher Copyright:
© 2021 Wiley-VCH GmbH
PY - 2021/5/10
Y1 - 2021/5/10
N2 - Nav1.5, the primary voltage-gated Na+ (Nav) channel in heart, is a major target for class I antiarrhythmic agents. Here we present the cryo-EM structure of full-length human Nav1.5 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 Nav1.5 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.
AB - Nav1.5, the primary voltage-gated Na+ (Nav) channel in heart, is a major target for class I antiarrhythmic agents. Here we present the cryo-EM structure of full-length human Nav1.5 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 Nav1.5 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.
KW - antiarrhythmic drugs
KW - cryo-EM structure
KW - quinidine
KW - voltage-gated Na (Na) channels
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U2 - 10.1002/anie.202102196
DO - 10.1002/anie.202102196
M3 - Article
C2 - 33684260
AN - SCOPUS:85103680842
SN - 1433-7851
VL - 60
SP - 11474
EP - 11480
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 20
ER -