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Increasing the molecular contacts between maurotoxin and Kv1.2 channel augments ligand affinity.

Abstract : Scorpion toxins interact with their target ion channels through multiple molecular contacts. Because a "gain of function" approach has never been described to evaluate the importance of the molecular contacts in defining toxin affinity, we experimentally examined whether increasing the molecular contacts between a toxin and an ion channel directly impacts toxin affinity. For this purpose, we focused on two scorpion peptides, the well-characterized maurotoxin with its variant Pi1-like disulfide bridging (MTX(Pi1)), used as a molecular template, and butantoxin (BuTX), used as an N-terminal domain provider. BuTX is found to be 60-fold less potent than MTX(Pi1) in blocking Kv1.2 (IC(50) values of 165 nM for BuTX versus 2.8 nM for MTX(Pi1)). Removal of its N-terminal domain (nine residues) further decreases BuTX affinity for Kv1.2 by 5.6-fold, which is in agreement with docking simulation data showing the importance of this domain in BuTX-Kv1.2 interaction. Transfer of the BuTX N-terminal domain to MTX(Pi1) results in a chimera with five disulfide bridges (BuTX-MTX(Pi1)) that exhibits 22-fold greater affinity for Kv1.2 than MTX(Pi1) itself, in spite of the lower affinity of BuTX as compared to MTX(Pi1). Docking experiments performed with the 3-D structure of BuTX-MTX(Pi1) in solution, as solved by (1)H-NMR, reveal that the N-terminal domain of BuTX participates in the increased affinity for Kv1.2 through additional molecular contacts. Altogether, the data indicate that acting on molecular contacts between a toxin and a channel is an efficient strategy to modulate toxin affinity.
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Contributor : Marco Canepari <>
Submitted on : Friday, January 22, 2010 - 3:32:03 PM
Last modification on : Friday, November 6, 2020 - 3:48:28 AM

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Sarrah M'Barek, Benjamin Chagot, Nicolas Andreotti, Violeta Visan, Pascal Mansuelle, et al.. Increasing the molecular contacts between maurotoxin and Kv1.2 channel augments ligand affinity.. Proteins - Structure, Function and Bioinformatics, Wiley, 2005, 60 (3), pp.401-11. ⟨10.1002/prot.20509⟩. ⟨inserm-00381749⟩



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