ArticleProceedings of the National Academy of Sciences of the United States of America2013
Multiple actions of phi-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 38 citations in OpenAlex.
- Review
- The Effect of Acidic Residues on the Binding between Opicalcin1 and Ryanodine Receptor from the Structure-Functional Analysis.Journal of natural products · 2024Article
- Venom-derived peptides for breaking through the glass ceiling of drug development.Frontiers in chemistry · 2024Review
- Small Molecules in the Venom of the ScorpionBiomedicines · 2020Article
- Scorpion Venom: Detriments and Benefits.Biomedicines · 2020Review
- Australian ScorpionBiomolecules · 2020Article
- Venoms of Iranian Scorpions (Arachnida, Scorpiones) and Their Potential for Drug Discovery.Molecules (Basel, Switzerland) · 2019Review
- Activation of RyR2 by class I kinase inhibitors.British journal of pharmacology · 2019Article
- Inhibitory Effect of an Acidic Peptide on the Activity of an Antimicrobial Peptide from the ScorpionMolecules (Basel, Switzerland) · 2018Article
- Transcriptomic and Proteomic Analyses Reveal the Diversity of Venom Components from the Vaejovid ScorpionToxins · 2018Article
- Article
- A Deeper Examination of Thorellius atrox Scorpion Venom Components with Omic Techonologies.Toxins · 2017Article
- Article
- Structural and Functional Elucidation of Peptide Ts11 Shows Evidence of a Novel Subfamily of Scorpion Venom Toxins.Toxins · 2016Article
- A sodium channel inhibitor ISTX-I with a novel structure provides a new hint at the evolutionary link between two toxin folds.Scientific reports · 2016Article
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We recently reported the isolation of a scorpion toxin named U1-liotoxin-Lw1a (U1-LITX-Lw1a) that adopts an unusual 3D fold termed the disulfide-directed hairpin (DDH) motif, which is the proposed evolutionary structural precursor of the three-disulfide-containing inhibitor cystine knot (ICK) motif found widely in animals and plants. Here we reveal that U1-LITX-Lw1a targets and activates the mammalian ryanodine receptor intracellular calcium release channel (RyR) with high (fM) potency and provides a functional link between DDH and ICK scorpion toxins. Moreover, U1-LITX-Lw1a, now described as ϕ-liotoxin-Lw1a (ϕ-LITX-Lw1a), has a similar mode of action on RyRs as scorpion calcines, although with significantly greater potency, inducing full channel openings at lower (fM) toxin concentrations whereas at higher pM concentrations increasing the frequency and duration of channel openings to a submaximal state. In addition, we show that the C-terminal residue of ϕ-LITX-Lw1a is crucial for the increase in full receptor openings but not for the increase in receptor subconductance opening, thereby supporting the two-binding-site hypothesis of scorpion toxins on RyRs. ϕ-LITX-Lw1a has potential both as a pharmacological tool and as a lead molecule for the treatment of human diseases that involve RyRs, such as malignant hyperthermia and polymorphic ventricular tachycardia.
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