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TitleStructure of the Cardiac Sodium Channel.
Journal, issue, pagesCell, Vol. 180, Issue 1, Page 122-134.e10, Year 2020
Publish dateJan 9, 2020
AuthorsDaohua Jiang / Hui Shi / Lige Tonggu / Tamer M Gamal El-Din / Michael J Lenaeus / Yan Zhao / Craig Yoshioka / Ning Zheng / William A Catterall /
PubMed AbstractVoltage-gated sodium channel Na1.5 generates cardiac action potentials and initiates the heartbeat. Here, we report structures of Na1.5 at 3.2-3.5 Å resolution. Na1.5 is distinguished from other ...Voltage-gated sodium channel Na1.5 generates cardiac action potentials and initiates the heartbeat. Here, we report structures of Na1.5 at 3.2-3.5 Å resolution. Na1.5 is distinguished from other sodium channels by a unique glycosyl moiety and loss of disulfide-bonding capability at the Naβ 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 Na1.5 structure, pharmacology, activation, inactivation, ion selectivity, and arrhythmias.
External linksCell / PubMed:31866066 / PubMed Central
MethodsEM (single particle)
Resolution3.24 - 3.5 Å
Structure data

20949

6uz0

EMDB-20949, PDB-6uz0:
Cardiac sodium channel with flecainide
Method: EM (single particle) / Resolution: 3.24 Å

20951

6uz3

EMDB-20951, PDB-6uz3:
Cardiac sodium channel
Method: EM (single particle) / Resolution: 3.5 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-9Z9:
(3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en / detergent*YM

ChemComp-6OU:
[(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate / phospholipid*YM

ChemComp-K4D:
Flecainide / medication*YM

Source
  • rattus norvegicus (Norway rat)
  • aequorea victoria (jellyfish)
KeywordsMETAL TRANSPORT / Cardiac sodium channel complex with flecainide / ion channel / cardiac sodium channel

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