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 - Funding Information:
We thank Xiaomin Li (Tsinghua University) for technical support during EM image acquisition. This work was funded by the National Key R&D Program (2016YFA0500402 to X.P.). We thank the Tsinghua University Branch of China National Center for Protein Sciences (Beijing) for providing the cryo‐EM facility support. We thank the computational facility support on the cluster of Bio‐Computing Platform (Tsinghua University Branch of China National Center for Protein Sciences Beijing) and the “Explorer 100” cluster system of Tsinghua National Laboratory for Information Science and Technology. N.Y. is supported by the Shirley M. Tilghman endowed professorship from Princeton University.
Funding Information:
We thank Xiaomin Li (Tsinghua University) for technical support during EM image acquisition. This work was funded by the National Key R&D Program (2016YFA0500402 to X.P.). We thank the Tsinghua University Branch of China National Center for Protein Sciences (Beijing) for providing the cryo-EM facility support. We thank the computational facility support on the cluster of Bio-Computing Platform (Tsinghua University Branch of China National Center for Protein Sciences Beijing) and the ?Explorer 100? cluster system of Tsinghua National Laboratory for Information Science and Technology. N.Y. is supported by the Shirley M. Tilghman endowed professorship from Princeton University.
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 -