Journal of Molecular Modeling

, Volume 12, Issue 6, pp 813–822 | Cite as

Modeling the pore structure of voltage-gated sodium channels in closed, open, and fast-inactivated conformation reveals details of site 1 toxin and local anesthetic binding

  • Holger ScheibEmail author
  • Iain McLay
  • Nicolas Guex
  • Jeff J. Clare
  • Frank E. Blaney
  • Tim J. Dale
  • Simon N. Tate
  • Graeme M. Robertson
Original Paper


In this work molecular modeling was applied to generate homology models of the pore region of the Na v 1.2 and Na v 1.8 isoforms of human voltage-gated sodium channels. The models represent the channels in the resting, open, and fast-inactivated states. The transmembrane portions of the channels were based on the equivalent domains of the closed and open conformation potassium channels KcsA and MthK, respectively. The critical selectivity loops were modeled using a structural template identified by a novel 3D-search technique and subsequently merged with the transmembrane portions. The resulting draft models were used to study the differences of tetrodotoxin binding to the tetrodotoxin-sensitive Na v 1.2 (EC50: 0.012 μM) and -insensitive Na v 1.8 (EC50: 60 μM) isoforms, respectively. Furthermore, we investigated binding of the local anesthetic tetracaine to Na v 1.8 (EC50: 12.5 μM) in resting, conducting, and fast-inactivated state. In accordance with experimental mutagenesis studies, computational docking of tetrodotoxin and tetracaine provided (1) a description of site 1 toxin and local anesthetic binding sites in voltage-gated sodium channels. (2) A rationale for site 1 toxin-sensitivity versus -insensitivity in atomic detail involving interactions of the Na v 1.2 residues F385-I and W943-II. (3) A working hypothesis of interactions between Na v 1.8 in different conformational states and the local anesthetic tetracaine.


Tetracaine in complex with Nav1.8 in fast-inactivated form. The ligand is represented in CPK and colored by atom type. Ribbons and amino acids are colored by domain: yellow = domain I, blue = domain II, green = domain III, red = domain IV, pink = inactivation gate. Main interaction partners are shown in CPK. a) Tetracaine bound to the inner vestibule. View along the membrane plane. b) Same view as in a but limited to main interaction partners only. The polar head group of tetracaine interacts with the DEKA-motif residues, its hydrophobic tail with the hydrophobic and mainly aromatic residues of S6-IV and the inactivation gate


Voltage-gated sodium channels Tetrodotoxin Tetracaine Protein structure modeling Computational docking 



HS thanks the Swiss Institute of Bioinformatics for support of this work. He also thanks GlaxoSmithKline for generous travel grants and a modified version of SPDBV.

Supplementary material

894_2005_66_MOESM1_ESM.pdf (20 kb)
Chemical structures of tetrodotoxin and tetracaine (PDF 20 kb)
894_2005_66_MOESM1_ESM.pdf (20 kb)
Residue names and numbers of amino acids forming the local anesthetic binding site in Nav1.2 and Nav1.8 (PDF 48kb)


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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Holger Scheib
    • 1
    • 2
    • 3
    Email author
  • Iain McLay
    • 4
  • Nicolas Guex
    • 5
  • Jeff J. Clare
    • 4
  • Frank E. Blaney
    • 6
  • Tim J. Dale
    • 4
  • Simon N. Tate
    • 4
  • Graeme M. Robertson
    • 7
  1. 1.SBC Lab AGWinkelSwitzerland
  2. 2.Department of Structural Biology and BioinformaticsUniversity of GenevaGeneva 4Switzerland
  3. 3.Swiss Institute of BioinformaticsCentre Médicale UniversitaireGeneva 4Switzerland
  4. 4.GlaxoSmithKline Medicines Research CentreStevenageUK
  5. 5.GlaxoSmithKlineResearch Triangle ParkUSA
  6. 6.GlaxoSmithKline New Frontiers Science Park (North)HarlowUK
  7. 7.sienabiotech SpASienaItaly

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