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Structural features important for the biological activity of the potassium channel blocking dendrotoxins

Hollecker, M and Marshall, D L and Harvey, A L (1993) Structural features important for the biological activity of the potassium channel blocking dendrotoxins. British Journal of Pharmacology, 110 (2). pp. 790-794. ISSN 0007-1188

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Dendrotoxins from mamba snake venoms are small proteins that block neuronal K+ channels. In order to investigate structural features associated with their biological activity, partially folded versions of dendrotoxins I and K from black mamba (Dendroaspis polylepis) were prepared by selectively reducing one or more of their three S-S bonds. The modified toxins were tested for ability to compete with 125I-labelled native toxin I to high affinity binding sites on rat brain synaptosomal membranes and for the ability to increase acetylcholine release in a neuromuscular preparation. Binding affinity increased progressively as the toxins folded to the native conformation and the most biologically active of the modified species were those in which only the disulphide bond between residues 14 and 38 was not formed. These intermediates had native-like conformations as determined by circular dichroism but still had about 5-10 times lower affinity than native toxins. Addition of negatively charged groups to block the free sulthydryls at positions 14 and 38 caused a further, marked loss of activity. The results are consistent with the existence of two important regions in the dendrotoxin molecules. The region containing two of the disulphide bonds (around Cys5-Cys55 and Cys30-Cys51) and much of the secondary structure is essential for the binding affinity of the toxins, while the region around Cys14 and Cys38, equivalent to part of the antiprotease site of the homologous protease inhibitor from bovine pancreas (BPTI), plays an important role in the potency of dendrotoxins.

Item type: Article
ID code: 31664
Keywords: animals, aprotinin, competitive binding, cell membrane, chick embryo, circular dichroism, elapid venoms, elapidae, iodine radioisotopes, muscles, neurons, neurotoxins, potassium channels, protein conformation, ultraviolet spectrophotometry, structure-activity relationship, synaptosomes, Pharmacy and materia medica, Pharmacology
Subjects: Medicine > Pharmacy and materia medica
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Depositing user: Pure Administrator
Date Deposited: 13 Jul 2011 08:56
Last modified: 10 Dec 2015 20:08

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