A variable residue in the pore of Kv1 channels is critical for the high affinity of Blockers from sea anemones and scorpions

被引:39
作者
Gilquin, B
Braud, S
Eriksson, MAL
Roux, B
Bailey, TD
Priest, BT
Garcia, ML
Ménez, A
Gasparini, S [1 ]
机构
[1] CEA Saclay, Dept Ingn & Etud Prot, F-91191 Gif Sur Yvette, France
[2] Cornell Univ, Weill Med Coll, Dept Biochem, New York, NY 10021 USA
[3] Merck Res Labs, Dept Ion Channels, Rahway, NJ 07065 USA
关键词
D O I
10.1074/jbc.M413626200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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., Menez, 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 Delta Delta G(int) 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.
引用
收藏
页码:27093 / 27102
页数:10
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