THE CRYSTAL STRUCTURE OF A VOLTAGE-GATED SODIUM CHANNEL
By J. Payandeh, T. Scheuer, Ning Zheng, William A. Catterall. Nature, 2011
1,365 citations recorded by the source corpus.
Voltage-gated sodium (NaV) channels initiate electrical signalling in excitable cells and are the molecular targets for drugs and disease mutations, but the structural basis for their voltage-dependent activation, ion selectivity and drug block is unknown. Here we report the crystal structure of a voltage-gated Na+ channel from Arcobacter butzleri (NavAb) captured in a closed-pore conformation with four activated voltage sensors at 2.7 Å resolution. The arginine gating charges make multiple hydrophilic interactions within the voltage sensor, including unanticipated hydrogen bonds to the protein backbone. Comparisons to previous open-pore potassium channel structures indicate that the voltage-sensor domains and the S4–S5 linkers dilate the central pore by pivoting together around a hinge at the base of the pore module. The NavAb selectivity filter is short, ∼4.6 Å wide, and water filled, with four acidic side chains surrounding the narrowest part of the ion conduction pathway. This unique structure presents a high-field-strength anionic coordination site, which confers Na+ selectivity through partial dehydration via direct interaction with glutamate side chains. Fenestrations in the sides of the pore module are unexpectedly penetrated by fatty acyl chains that extend into the central cavity, and these portals are large enough for the entry of small, hydrophobic pore-blocking drugs. This structure provides the template for understanding electrical signalling in excitable cells and the actions of drugs used for pain, epilepsy and cardiac arrhythmia at the atomic level.
Subfields: Cellular and Molecular Neuroscience, Electrochemistry, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/5b98fc8a25642d5b2d0164ba59630e68f63eb96a
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In Cellular and Molecular Neuroscience
In Electrochemistry
In Molecular Biology
- Jose M. Duarte
- William A. Catterall
- Stephen K. Burley
- Christine Zardecki
- David S. Goodsell
- John D. Westbrook
- Jie Zheng
- M. Trudeau
Citations in the corpus
- Voltage‐gated sodium channels at 60: structure, function and pathophysiology (2012, background): “This initial view of pore structure of sodium channels has been illuminated at the atomic level by the structure of the NavAb channel (Payandeh et al. 2011).”
- RCSB Protein Data Bank: Enabling biomedical research and drug discovery (2019, background): “50 In contrast, the mammalian channel is composed of one long alpha chain, which forms four membrane-spanning domains similar in arrangement to the four identical bacterial subunits.”
- A lysine residue from an extracellular turret switches the ion preference in a Cav3 T-Type channel from calcium to sodium ions (2022, background): “1) in the L6 extracellular loop of extended length in some (16) but lacking in other (17,18) bacterial homologs (Fig.”