6LQA

voltage-gated sodium channel Nav1.5 with quinidine

Summary for 6LQA

• Entry DOI: 10.2210/pdb6lqa/pdb
• EMDB information: 0942
• Descriptor: Sodium channel protein type 5 subunit alpha, 2-acetamido-2-deoxy-beta-D-glucopyranose, Quinidine (3 entities in total)
• Functional Keywords: membrane protein, voltage-gated sodium channel, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 234059.23

Authors

Yan, N.,Li, Z.,Pan, X.,Huang, G. (deposition date: 2020-01-13, release date: 2021-03-24, Last modification date: 2024-11-06)

Primary citation

Li, Z.,Jin, X.,Wu, T.,Huang, G.,Wu, K.,Lei, J.,Pan, X.,Yan, N.
Structural Basis for Pore Blockade of the Human Cardiac Sodium Channel Na v 1.5 by the Antiarrhythmic Drug Quinidine*.
Angew.Chem.Int.Ed.Engl., 60:11474-11480, 2021

PubMed Abstract: 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.

PubMed: 33684260
DOI: 10.1002/anie.202102196

Experimental method

ELECTRON MICROSCOPY (3.3 Å)