Key amino acid residues involved in mammalian and insecticidal activities of Magi4 and Hv1b, cysteine-rich spider peptides from the δ-atracotoxin family
| Autor: | Iván Arenas, Herlinda Clement, Gerardo Corzo, Jesús Borrego, Ligia-Luz Corrales-García |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Insecticides Amino Acid Motifs Neurotoxins Clinical Biochemistry Spider Venoms Biochemistry law.invention Gryllidae Lethal Dose 50 Mice 03 medical and health sciences Protein Domains law medicine Animals Neurotoxin Amino Acid Sequence Amino Acids chemistry.chemical_classification 030102 biochemistry & molecular biology Chemistry Sodium channel Organic Chemistry Biological activity Recombinant Proteins Amino acid 030104 developmental biology Amino Acid Substitution Mechanism of action Recombinant DNA Pharmacophore medicine.symptom Cysteine |
| Zdroj: | Amino Acids. 52:465-475 |
| ISSN: | 1438-2199 0939-4451 |
| DOI: | 10.1007/s00726-020-02825-4 |
| Popis: | δ-Atracotoxins, also known as δ-hexatoxins, are spider neurotoxic peptides, lethal to both vertebrates and insects. Their mechanism of action involves the binding to of the S3/S4 loop of the domain IV of the voltage-gated sodium channels (Nav). Because of the chemical difficulties of synthesizing folded synthetic δ-atracotoxins correctly, here we explore an expression system that is designed to produce biologically active recombinant δ-atracotoxins, and a number of variants, in order to establish certain amino acids implicated in the pharmacophore of this lethal neurotoxin. In order to elucidate and verify which amino acid residues play a key role that is toxic to vertebrates and insects, amino acid substitutes were produced by aligning the primary structures of several lethal δ-atracotoxins with those of δ-atracotoxins-Hv1b; a member of the δ-atracotoxin family that has low impact on vertebrates and is not toxic to insects. Our findings corroborate that the substitutions of the amino acid residue Y22 from δ-atracotoxin-Mg1a (Magi4) to K22 in δ-atracotoxin-Hv1b reduces its mammalian activity. Moreover, the substitutions of the amino acid residues Y22 and N26 from δ-atracotoxin-Mg1a (Magi4) to K22 and N26 in δ-atracotoxin-Hv1b reduces its insecticidal activity. Also, the basic residues K4 and R5 are important for keeping such insecticidal activity. Structural models suggest that such residues are clustered onto two bioactive surfaces, which share similar areas, previously reported as bioactive surfaces for scorpion α-toxins. Furthermore, these bioactive surfaces were also found to be similar to those found in related spider and anemone toxins, which affect the same Nav receptor, indicating that these motifs are important not only for scorpion but may be also for animal toxins that affect the S3/S4 loop of the domain IV of the Nav. |
| Databáze: | OpenAIRE |
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