Structural Basis for Pore Blockade of the Human Cardiac Sodium Channel Nav1.5 by the Antiarrhythmic Drug Quinidine. Issue 20 (6th April 2021)

• Record Type: Journal Article
• Authors: Li, Zhangqiang; Jin, Xueqin; Wu, Tong; Huang, Gaoxingyu; Wu, Kun; Lei, Jianlin; Pan, Xiaojing; Yan, Nieng
• Is Part Of: Angewandte Chemie international edition. Volume 60:Issue 20(2021)
• Page Start: 11474
• Page End: 11480
• Publication Date: 2021-04-06
• Subjects: antiarrhythmic drugs -- cryo-EM structure -- quinidine -- voltage-gated Na+ (Nav) channels; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202102196
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Nav 1.5, 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 Nav 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 Nav 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. Abstract : The Cryo‐EM structure of human cardiac sodium channel Nav 1.5 in complex with quinidine reveals the molecular basis for pore blockade of Nav 1.5 by class Ic antiarrhythmic drugs. An advanced and comprehensive structural understanding of the mechanism of action of antiarrhythmic drugs will facilitate drug discovery targeting Nav channels.