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Structure-Function Relationship of a Novel MTX-like Peptide (MTX1) Isolated and Characterized from the Venom of the
Rym ElFessi1, Oussema Khamessi1,2, Michel De Waard3
1Laboratory of Venoms and Therapeutic Biomolecules, Pasteur Institute of Tunis, University of Tunis El Manar, 13 Place Pasteur, BP74, Tunis 1002, Tunisia.
Abstract:
Maurotoxin (MTX) is a 34-residue peptide from Scorpio maurus venom. It is reticulated by four disulfide bridges with a unique arrangement compared to other scorpion toxins that target potassium (K+) channels. Structure-activity relationship studies have not been well performed for this toxin family. The screening of Scorpio maurus venom was performed by different steps of fractionation, followed by the ELISA test, using MTX antibodies, to isolate an MTX-like peptide. In vitro, in vivo and computational studies were performed to study the structure-activity relationship of the new isolated peptide. We isolated a new peptide designated MTX1, structurally related to MTX. It demonstrated toxicity on mice eight times more effectively than MTX. MTX1 blocks the Kv1.2 and Kv1.3 channels, expressed in Xenopus oocytes, with IC50 values of 0.26 and 180 nM, respectively. Moreover, MTX1 competitively interacts with both 125I-apamin (IC50 = 1.7 nM) and 125I-charybdotoxin (IC50 = 5 nM) for binding to rat brain synaptosomes. Despite its high sequence similarity (85%) to MTX, MTX1 exhibits a higher binding affinity towards the Kv1.2 and SKCa channels. Computational analysis highlights the significance of specific residues in the β-sheet region, particularly the R27, in enhancing the binding affinity of MTX1 towards the Kv1.2 and SKCa channels.
Insights
Researchers discovered a new scorpion toxin, MTX1, which is eight times more toxic than Maurotoxin (MTX). MTX1 shows enhanced binding affinity to potassium channels, offering new insights into toxin structure-activity relationships.
Area of Science:
- Biochemistry
- Pharmacology
- Neuroscience
Background:
- Maurotoxin (MTX) is a scorpion toxin targeting potassium (K+) channels, but its structure-activity relationships are poorly understood.
- Scorpion venom toxins are valuable tools for studying ion channel function.
Purpose of the Study:
- To isolate and characterize novel MTX-like peptides from Scorpio maurus venom.
- To investigate the structure-activity relationship of a newly isolated peptide, MTX1.
Main Methods:
- Fractionation of Scorpio maurus venom and ELISA screening using MTX antibodies.
- In vitro and in vivo toxicity assays in mice.
- Xenopus oocyte expression system to study Kv1.2 and Kv1.3 channel blockade.
- Radioligand binding assays using 125I-apamin and 125I-charybdotoxin on rat brain synaptosomes.
- Computational analysis of MTX1 structure and binding interactions.
Main Results:
- A novel MTX-like peptide, MTX1, was isolated.
- MTX1 demonstrated eightfold higher toxicity in mice compared to MTX.
- MTX1 potently blocked Kv1.2 (IC50 = 0.26 nM) and Kv1.3 (IC50 = 180 nM) channels.
- MTX1 exhibited high affinity for Kv1.2 and SKCa channels, with competitive binding to 125I-apamin and 125I-charybdotoxin.
- Computational analysis identified specific residues, like R27, crucial for enhanced binding affinity.
Conclusions:
- MTX1 represents a potent new scorpion toxin with significant activity against Kv1.2 and SKCa channels.
- The study elucidates key structural determinants of MTX1's enhanced binding affinity, advancing understanding of scorpion toxin SAR.
- MTX1 serves as a valuable pharmacological tool for investigating potassium channel function.
