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Protein Science (2004), 13:1197-1208. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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Solution structure of Phrixotoxin 1, a specific peptide inhibitor of Kv4 potassium channels from the venom of the theraphosid spider Phrixotrichus auratus

Benjamin Chagot1, Pierre Escoubas2, Elba Villegas3, Cédric Bernard1, Gilles Ferrat1,3, Gerardo Corzo3, Michel Lazdunski2 and Hervé Darbon1

1 Architecture et Fonction des Macromolécules Biologiques (AFMB), Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 6098 and Universités d’Aix-Marseille I and II, 13402 Marseille Cedex 20, France
2 Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique (CNRS), UMR 6097, Sophia-Antipolis, 06560 Valbonne, France
3 Suntory Institute for Bioorganic Research, Mishima-Gun, Shimamoto-Cho, Wakayamadai 1–1–1, Osaka 618-8503, Japan

(RECEIVED December 18, 2003; FINAL REVISION February 3, 2004; ACCEPTED February 3, 2004)



Abstract

Animal toxins block voltage-dependent potassium channels (Kv) either by occluding the conduction pore (pore blockers) or by modifying the channel gating properties (gating modifiers). Gating modifiers of Kv channels bind to four equivalent extracellular sites near the S3 and S4 segments, close to the voltage sensor. Phrixotoxins are gating modifiers that bind preferentially to the closed state of the channel and fold into the Inhibitory Cystine Knot structural motif. We have solved the solution structure of Phrixotoxin 1, a gating modifier of Kv4 potassium channels. Analysis of the molecular surface and the electrostatic anisotropy of Phrixotoxin 1 and of other toxins acting on voltage-dependent potassium channels allowed us to propose a toxin interacting surface that encompasses both the surface from which the dipole moment emerges and a neighboring hydrophobic surface rich in aromatic residues.

Keywords: Phrixotoxin 1; NMR; spider toxin; structure determination; potassium channel gating modifier

Reprint requests to: Hervé Darbon, AFMB, CNRS, UMR 6098 and Universités d’Aix-Marseille I and II, 31 Chemin Joseph Aiguier, 13402 Marseille Cedex 20, France; e-mail: herve{at}afmb.cnrs-mrs.fr; fax: +33 (0)4-91-16-45-36; or Pierre Escoubas, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS, UMR 6097, 660 Route des Lucioles, Sophia-Antipolis, 06560 Valbonne, France; e-mail: escoubas{at}ipmc.cnrs.fr; fax +33 (0)4-93-95-77-08.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03584304.


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