title: A variable residue in the pore of Kv1 channels is critical for the high affinity of blockers from sea anemones and scorpions.
abstract: Animal toxins are associated with well defined selectivity profiles; however the molecular basis for this property is not understood. To address this issue we refined our previous three-dimensional models of the complex between the sea anemone toxin BgK and the S5-S6 region of Kv1.1 (Gilquin, B., Racape, J., Wrisch, A., Visan, V., Lecoq, A., Grissmer, S., Ménez, A., and Gasparini, S. (2002) J. Biol. Chem. 277, 37406-37413) using a docking procedure that scores and ranks the structures by comparing experimental and back-calculated values of coupling free energies DeltaDeltaGint obtained from double-mutant cycles. These models further highlight the interaction between residue 379 of Kv1.1 and the conserved dyad tyrosine residue of BgK. Because the nature of the residue at position 379 varies from one channel subtype to another, we explored how these natural mutations influence the sensitivity of Kv1 channel subtypes to BgK using binding and electrophysiology experiments. We demonstrated that mutations at this single position indeed suffice to abolish or enhance the sensitivity of Kv1 channels for BgK and other sea anemone and scorpion toxins. Altogether, our data suggest that the residue at position 379 of Kv1 channels controls the affinity of a number of blocking toxins.
authors.affiliation: Département d'Ingénierie et d'Etudes des Protéines, Commissariat à l'Energie Atomique Saclay, 91191 Gif sur Yvette cedex, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Gilquin
authors.forename: Sandrine
authors.initials: S
authors.lastname: Braud
authors.forename: Mats A L
authors.initials: MA
authors.lastname: Eriksson
authors.forename: Benoît
authors.initials: B
authors.lastname: Roux
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Bailey
authors.forename: Birgit T
authors.initials: BT
authors.lastname: Priest
authors.forename: Maria L
authors.initials: ML
authors.lastname: Garcia
authors.forename: André
authors.initials: A
authors.lastname: Ménez
authors.forename: Sylvaine
authors.initials: S
authors.lastname: Gasparini
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D003064:Cnidarian Venoms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D051662:Kv1.1 Potassium Channel; D008958:Models, Molecular; D009154:Mutation; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D012605:Scorpions; D012615:Sea Anemones; D051637:Shaker Superfamily of Potassium Channels; D014162:Transfection
chemical_list: D003064:Cnidarian Venoms; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051637:Shaker Superfamily of Potassium Channels; C104455:toxin BgK; D051662:Kv1.1 Potassium Channel