Molecular modeling of scorpion toxin binding to voltage-gated K+ channels


Mutational studies have identified part of the S5-S6 loop of voltage-dependent K+ channels (P region) responsible for tetraethylammonium (TEA) block and permeation properties. Several scorpion peptide toxins – charybdotoxin (ChTX), kaliotoxin (KITX), and agitoxin (AgTX) – also block the channel with high affinity and specificity. An interaction surface for the toxins has been identified by mutation-induced alteration in toxin binding, and some of the interaction partners have been identified by mutation of channel residues using mutant cycle analysis. This has provided a general picture for the channel vestibule. Here, we examine the interaction predicted when the scorpion toxins are docked onto a molecular model of the K+ channel pore (the Kv1.3 isoform) that we recently proposed [1]. In the optimal alignment of the toxin with the pore, Arg-24 of KITX or AgTX forms a hydrogen bond with the Asp-386 carboxyl of one subunit, and Asn-30 is in immediate contact with Asp-386 of the opposing subunit in the channel tetramer. Toxin residues in proximity to the side chain of Lys-27 (Phe-25, Thr-36, Met-29, and Ser-11 in KITX) interact with the outer ring of four C-end His-404 residues. For ChTX the interaction with Asp-386 is reduced, but this is compensated by additional non-bonded interactions formed by Tyr-36 and Arg-34. Comparison of calculated energy of interaction of these specific toxin-channel residue pairs with experimental studies reveals good agreement. The similar total calculated energy of interaction is consistent with the similar IC50 for Kv1.3 block by KITX and ChTX. Molecular modeling shows complementarity of the pore model to toxin spatial structures, and contributes to our understanding of the surface topology to the K+ channel outer vestibule.

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  1. 1.

    Lipkind, G.M., Hanck, D.A. and Fozzard, H.A., Proc. Natl. Acad. Sci. USA, 92 (1995) 9215.

    Google Scholar 

  2. 2.

    Pongs, O., Physiol. Rev., 72 (1992) S69.

    Google Scholar 

  3. 3.

    Kukuljan, M., Labarca, P. and Latorre, R., Am. J. Physiol. (Cell Physiol.), 268 (1995) C535.

    Google Scholar 

  4. 4.

    Guy, H.R. and Conti, F., TINS, 13 (1990) 201.

    Google Scholar 

  5. 5.

    MacKinnon, R. and Yellen, G., Science, 250 (1990) 276.

    Google Scholar 

  6. 6.

    Yellen, G., Jurman, M.E., Abramson, T. and MacKinnon, R., Science, 251 (1991) 939.

    Google Scholar 

  7. 7.

    Yool, A.J. and Schwarz, T.L., Nature, 349 (1991) 700.

    Google Scholar 

  8. 8.

    Chandy, K.G. and Gutman, G.A., in R.A. North (Ed.), Handbook of Receptors and Channels: Ligand-and Voltage-gated Ion Channels, 1st ed., CRC Press, Boca Raton, FL, 1995, pp. 1–72.

    Google Scholar 

  9. 9.

    MacKinnon, R. and Miller, C., J. Gen. Physiol., 91 (1988) 335.

    Google Scholar 

  10. 10.

    Miller, C., Neuron, 1 (1988) 1003.

    Google Scholar 

  11. 11.

    Park, C.S. and Miller, C., Biochemistry 31 (1992) 7749.

    Google Scholar 

  12. 12.

    Miller, C., Neuron, 15 (1995) 5.

    Google Scholar 

  13. 13.

    Bontems, F., Roumestand, C., Gilquin, B., Menez, A. and Toma, F., Science, 254 (1991) 1521.

    Google Scholar 

  14. 14.

    Krezel, A., Kasibhatla, C., Hidalgo, P., MacKinnon, R. and Wagner, G., Protein Sci., 4 (1995) 1478.

    Google Scholar 

  15. 15.

    Aiyar, J., Withka, J.M., Rizzi, J.P., Singleton, D.H., Andrews, G.C., Lin, W., Boyd, J., Hanson, D.C., Simon, M., Dethlefs, B., Lee, C.L., Hall, J.E., Gutman, G.A. and Chandy, K.G., Neuron, 15 (1995) 1169.

    Google Scholar 

  16. 16.

    Goldstein, S.A.N. and Miller, C., Biophys. J., 62 (1992) 5.

    Google Scholar 

  17. 17.

    Goldstein, S.A.N. and Miller, C., Biophys. J., 65 (1993) 1613.

    Google Scholar 

  18. 18.

    Goldstein, S.A.N., Pheasant, D.J. and Miller, C., Neuron, 12 (1994) 1377.

    Google Scholar 

  19. 19.

    Ranganathan, R., Lewis, J.H. and MacKinnon, R., Neuron, 12 (1994) 1377.

    Google Scholar 

  20. 20.

    Hidalgo, P. and MacKinnon, R., Science, 268 (1995) 307.

    Google Scholar 

  21. 21.

    Naranjo, D. and Miller, C., Neuron, 16 (1996) 123.

    Google Scholar 

  22. 22.

    Harper, E.T. and Rose, G.D., Biochemistry, 32 (1993) 7605.

    Google Scholar 

  23. 23.

    Gross, A. and MacKinnon, R., Neuron, 16 (1996) 399.

    Google Scholar 

  24. 24.

    Lipkind, G.M. and Fozzard, H.A., J. Membrane Biol., 158 (1997) 187.

    Google Scholar 

  25. 25.

    Lipkind, G.M. and Fozzard, H.A., Biophys. J., 66 (1994) 1.

    Google Scholar 

  26. 26.

    Dudley, Jr., S.C., Todt, H., Lipkind, G. and Fozzard, H.A., Biophys. J., 69 (1995) 1657.

    Google Scholar 

  27. 27.

    Klotz, I.M. and Fransen, J.S., J. Am. Chem. Soc., 84 (1962) 3461.

    Google Scholar 

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Correspondence to Harry A. Fozzard.

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Lipkind, G.M., Fozzard, H.A. Molecular modeling of scorpion toxin binding to voltage-gated K+ channels. Perspectives in Drug Discovery and Design 15, 245–255 (1999).

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  • molecular models
  • mutant cycle analysis
  • point mutations
  • potassium channel
  • scorpion toxins