Journal
CELL
Volume 180, Issue 1, Pages 122-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2019.11.041
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Funding
- NIH [R01 HL112808]
- Howard Hughes Medical Institute
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Voltage-gated sodium channel Na(v)1.5 generates cardiac action potentials and initiates the heartbeat. Here, we report structures of Na(V)1.5 at 3.2-3.5 angstrom resolution. Na(V)1.5 is distinguished from other sodium channels by a unique glycosyl moiety and loss of disulfide-bonding capability at the Na-V beta subunit-interaction sites. The antiarrhythmic drug flecainide specifically targets the central cavity of the pore. The voltage sensors are partially activated, and the fast-inactivation gate is partially closed. Activation of the voltage sensor of Domain III allows binding of the isoleucine-phenylalanine-methionine (IFM) motif to the inactivation-gate receptor. Asp and Ala, in the selectivity motif DEKA, line the walls of the ion-selectivity filter, whereas Glu and Lys are in positions to accept and release Na+ ions via a charge-delocalization network. Arrhythmia mutation sites undergo large translocations during gating, providing a potential mechanism for pathogenic effects. Our results provide detailed insights into Na(v)1.5 structure, pharmacology, activation, inactivation, ion selectivity, and arrhythmias.
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