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- W1966967564 abstract "Potent and selective modulators are needed to elucidate the individual roles of ion channel subtypes in physiological systems. Many cystine knot peptides derived from tarantula venom allosterically modulate voltage sensors of ion channels. Although tarantula peptides have varying affinities for different channels, all affect multiple subtypes. Theoretically, a peptide's selectivity between channel types could be amplified by summing binding energies, if a multimeric version of the peptide could bind multiple subunits simultaneously. We have amplified the inherent specificity of a voltage sensor peptide, guangxitoxin-1E (GxTX), by tethering two peptides together to form a dimer coupled by a flexible polyethylene glycol linker. We synthesized GxTX mutants functionalized with artificial amino acids for chemoselective coupling and tethered them with homobifunctional linkers using azide-alkyne cycloaddition chemistry. The GxTX dimers inhibited Kv2.1 with higher affinity than GxTX monomers. Similar to GxTX monomers, these tethered dimers shifted channel opening to positive voltages. Association rates were reduced for the GxTX dimers versus monomers, indicating that increased affinity for Kv2.1 channels was entirely due to the extremely slow dissociation of GxTX dimers. The strong voltage dependence of dimer dissociation was consistent with a two step binding model, where the kinetics of the second GxTX binding domain determines the amplification of affinity by the dimer. This mechanism predicts that dimerization will selectively amplify the affinity for channels with slow toxin dissociation rates. Experimentally, dimerization amplified GxTX specificity for Kv2.1 over other channel subtypes. We conclude that tethered multimers can increase the pharmacological selectivity of voltage sensor modulators." @default.
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- W1966967564 date "2014-01-01" @default.
- W1966967564 modified "2023-09-29" @default.
- W1966967564 title "Tethering Dimers of Voltage Sensor Toxins can Selectively Amplify their Affinity for Kv Channels" @default.
- W1966967564 doi "https://doi.org/10.1016/j.bpj.2013.11.568" @default.
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