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The crystal structure of a voltage-gated sodium channel

Nature volume 475, pages 353358 (21 July 2011) | Download Citation

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Abstract

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.

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Change history

  • 20 July 2011

    A PDB accession code was corrected

Accessions

Primary accessions

Data deposits

Coordinates and structure factors have been deposited in the Protein Data Bank under accession codes 3RVY, 3RVZ and 3RW0.

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Acknowledgements

We thank B. Hille for comments on a draft of the manuscript and members of the N.Z. and W.A.C. groups for their support throughout this project. We are grateful to investigators who provided genomic DNA and the beamline staff at the Advanced Light Source (BL8.2.1 and BL8.2.2) for their assistance during data collection. J.P. acknowledges support from a Canadian Institutes of Health Research fellowship and the encouragement of E. Payandeh. This work was supported by grants from the National Institutes of Health (R01 NS15751 and U01 NS058039 to W.A.C.) and by the Howard Hughes Medical Institute (N.Z.).

Author information

Affiliations

  1. Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA

    • Jian Payandeh
    • , Todd Scheuer
    • , Ning Zheng
    •  & William A. Catterall
  2. Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA

    • Ning Zheng

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Contributions

N.Z. and W.A.C. are co-senior authors. J.P., N.Z. and W.A.C. conceived and J.P. conducted the protein purification and crystallization experiments. J.P. and N.Z. determined and analysed the structures of NavAb. J.P. and T.S. performed functional studies of NavAb. J.P., N.Z. and W.A.C. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ning Zheng or William A. Catterall.

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    Supplementary Information

    The file contains Supplementary Table 1, Supplementary Discussion, Supplementary Figures 1-13 with legends and additional references.

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https://doi.org/10.1038/nature10238

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