Structural Basis for Pore Blockade of the Human Cardiac Sodium Channel Na v 1.5 by the Antiarrhythmic Drug Quinidine**
| Autor: | Nieng Yan, Jianlin Lei, Zhangqiang Li, Gaoxingyu Huang, Xiaojing Pan, Tong Wu, Kun Wu, Xueqin Jin |
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| Rok vydání: | 2021 |
| Předmět: |
Quinidine
Drug biology 010405 organic chemistry Chemistry media_common.quotation_subject Sodium channel General Chemistry General Medicine Nav1.5 Pharmacology 010402 general chemistry 01 natural sciences Catalysis 0104 chemical sciences Blockade Mechanism of action Biophysics biology.protein medicine medicine.symptom Flecainide Intracellular medicine.drug media_common |
| Zdroj: | Angewandte Chemie. 133:11575-11581 |
| ISSN: | 1521-3757 0044-8249 |
| DOI: | 10.1002/ange.202102196 |
| Popis: | Na v 1.5, the primary voltage-gated Na + (Na v ) channel in heart, is a major target for class I antiarrhythmic agents. Here we present the cryo-EM structure of full-length human Na v 1.5 bound to quinidine, a class Ia antiarrhythmic drug, at 3.3 A 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 v 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. |
| Databáze: | OpenAIRE |
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