ArticleMolecular pharmacology2009
S3b amino acid substitutions and ancillary subunits alter the affinity of Heteropoda venatoria toxin 2 for Kv4.3.
Article in Molecular pharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 25 citations in OpenAlex.
- Acute arsenic trioxide inhibits the cardiac transient outward KCurrent research in structural biology · 2026Article
- Optimizing Nav1.7-Targeted Analgesics: Revealing Off-Target Effects of Spider Venom-Derived Peptide Toxins and Engineering Strategies for Improvement.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Design of Ultrapotent Genetically Encoded Inhibitors of Kv4.2 for Gating Neural Plasticity.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Effects of JZTX-V on the wild type Kv4.3 Expressed in HEK293T and Molecular Determinants in the Voltage-sensing Domains of Kv4.3 Interacting with JZTX-V.Channels (Austin, Tex.) · 2022Article
- Molecular mechanism of the spider toxin κ-LhTx-I acting on the bacterial voltage-gated sodium channel NaChBac.Frontiers in pharmacology · 2022Article
- Peptide Inhibitors of Kv1.5: An Option for the Treatment of Atrial Fibrillation.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Variation of Two S3b Residues in KFrontiers in pharmacology · 2021Article
- Peptide Toxins Targeting KV Channels.Handbook of experimental pharmacology · 2021Review
- Article
- JZTX-V Targets the Voltage Sensor in Kv4.2 to Inhibit IFrontiers in pharmacology · 2019Article
- Kv Channel S1-S2 Linker Working as a Binding Site of Human β-Defensin 2 for Channel Activation Modulation.The Journal of biological chemistry · 2015Article
- Characterization of SEMA3A-encoded semaphorin as a naturally occurring Kv4.3 protein inhibitor and its contribution to Brugada syndrome.Circulation research · 2014Article
- Inhibition of A-type potassium current by the peptide toxin SNX-482.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2014Article
- Computational methods of studying the binding of toxins from venomous animals to biological ion channels: theory and applications.Physiological reviews · 2013Review
- Targeting ion channels for the treatment of gastrointestinal motility disorders.Therapeutic advances in gastroenterology · 2012Article
- Voltage sensor inactivation in potassium channels.Frontiers in pharmacology · 2012Article
- A-type K+ currents in intralaminar thalamocortical relay neurons.Pflugers Archiv : European journal of physiology · 2011Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Heteropoda venatoria toxin 2 (HpTx2) is an inhibitor cystine knot (ICK)-gating modifier toxin that selectively inhibits Kv4 channels. To characterize the molecular determinants of interaction, we performed alanine scanning of the Kv4.3 S3b region. HpTx2-Kv4.3 interaction had an apparent K(d) value of 2.3 microM. Two alanine mutants in Kv4.3 increased K(d) values to 6.4 microM for V276A and 25 microM for L275A. Simultaneous mutation of both amino acids to alanine nearly eliminated toxin interaction. Unlike Hanatoxin and other well characterized ICK toxins, HpTx2 binding does not require a charged amino acid for interaction. To determine whether the identity of the S3b binding site amino acids altered HpTx2 specificity, we constructed Kv4.3 [LV275IF]. This mutation decreased the K(d) value to 0.54 microM, suggesting that the hydrophobic character of the putative binding site is the most important property for interaction with HpTx2. One mutant, N280A, caused stronger interaction of HpTx2 with Kv4.3; the K(d) value for Kv4.3 [N280A] was 0.26 microM. To understand Kv4.3-based transient outward currents in native tissues, we tested the affinity of HpTx2 for Kv4.3 coexpressed with KChIP2b. The toxin's K(d) value for Kv4.3 + KChIP2b was 0.95 microM. KChIP2b stabilizes the closed state of Kv4.3, suggesting that the increased toxin affinity is due to increased stabilization of the closed state. These data show that HpTx2 binding to Kv4.3 has aspects in common with other ICK gating modifier toxins but that the interventions that increase toxin affinity suggest flexibility toward channel binding that belies its unusual specificity for Kv4 channels.
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