Anuroctoxin and its interaction with voltage-gated K+ ion channels Kv1.2 and Kv1.3

The voltage-gated Kv1.3 potassium channel plays a key role in the activation of T lymphocytes. By blocking these channels the proliferation of T cells can be inhibited thus suppressing T-cell mediated immune responses, which has a great potential in the therapy of certain autoimmune diseases. Anuroctoxin (1) is a 35-amino acid scorpion peptide characterized previously as a high affinity blocker of Kv1.3. Although with lower affinity, Anuroctoxin blocks Kv1.2 as well, which is expressed in several tissues, thus this property limits the potential clinical use of the toxin. In order to design new mutants of Anuroctoxin with improved selectivity profile, a detailed understanding of its interaction with voltage gated K+ ion channels is needed. We have prepared synthetic analogue of Anuroctoxin with solid phase synthesis and verified its activity with Kv1.2 and Kv1.3 channels. We have determined the solution structure of Anuroctxin using homonuclear NMR techniques and molecular dynamic simulations. The determinants of its interaction with Kv1.2 and Kv1.3 channels have been investigated and explored with docking calculations. Our results provide data for the design and future therapeutic application of new, more selective peptide toxins. References 1. Bagdany M, Batista CV, Valdez-Cruz NA, Somodi S, Rodriguez de la Vega RC, Licea AF, et al. Anuroctoxin, a new scorpion toxin of the alpha-KTx 6 subfamily, is highly selective for Kv1.3 over IKCa1 ion channels of human T lymphocytes. Mol Pharmacol 2005;67:1034-44