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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Looking over Toxin-K+ Channel Interactions. Clues from the Structural and Functional Characterization of alpha-KTx Toxin Tc32, a Kv1.3 Channel Blocker

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Author(s):
Stehling, Eliana G. [1] ; Sforca, Mauricio L. [2] ; Zanchin, Nilson I. T. [2] ; Oyama, Jr., Sergio [2] ; Pignatelli, Angela [3] ; Belluzzi, Ottorino [3] ; Polverini, Eugenia [4] ; Corsini, Romina [5] ; Spisni, Alberto [5] ; Pertinhez, Thelma A. [5]
Total Authors: 10
Affiliation:
[1] USP, Dept Toxicol & Bromatol Clin Anal, Fac Pharmaceut Sci Ribeirao Preto, Ribeirao Preto - Brazil
[2] Natl Lab Biosci, Campinas, SP - Brazil
[3] Univ Ferrara, Dept Biol & Evolut, Physiol & Biophys Unit, I-44100 Ferrara - Italy
[4] Univ Parma, Dept Phys, I-43125 Parma - Italy
[5] Univ Parma, Dept Expt Med, Chem & Struct Biochem Unit, I-43125 Parma - Italy
Total Affiliations: 5
Document type: Journal article
Source: BIOCHEMISTRY; v. 51, n. 9, p. 1885-1894, MAR 6 2012.
Web of Science Citations: 8
Abstract

alpha-KTx toxin Tc32, from the Amazonian scorpion Tityus cambridgei, lacks the dyad motif; including Lys27, characteristic of the family and generally associated with channel blockage. The toxin has been cloned and expressed for the first time. Electrophysiological experiments, by showing that the recombinant form blocks Kv1.3 channels of olfactory bulb periglomerular cells like the natural Tc32 toxin, when tested on the Kv1.3 channel of human T lymphocytes, confirmed it is in an active fold. The nuclear magnetic resonance-derived structure revealed it exhibits an alpha/beta scaffold typical of the members of the alpha-KTx family. TdK2 and TdK3, all belonging to the same alpha-KTx 18 subfamily, share significant sequence identity with Tc32 but diverse selectivity and affinity for Kv1.3 and Kv1.1 channels. To gain insight into the structural features that may justify those differences, we used the recombinant Tc32 nuclear magnetic resonance-derived structure to model the other two toxins, for which no experimental structure is available. Their interaction with Kv1.3 and Kv1.1 has been investigated by means of docking simulations. The results suggest that differences in the electrostatic features of the toxins and channels, in their contact surfaces, and in their total dipole moment orientations govern the affinity and selectivity of toxins. In addition, we found that, regardless of whether the dyad motif is present, it is always a Lys side chain that physically blocks the channels, irrespective of its position in the toxin sequence. (AU)

FAPESP's process: 00/10266-8 - A structural biology laboratory network for the study of the 3D structures of proteins
Grantee:Nilson Ivo Tonin Zanchin
Support Opportunities: Genome Research Grants