ß-toxin insecticide · The ß-scorpion toxin binding site as a potential target for new insecticides

Effective pest control is essential for human health, prosperity and food security. The development of insecticide resistance threatens agriculture and health programmes, where insect vectors spread life-threatening diseases such as malaria. Therefore there is a continuous need for new, effective and environmentally-friendly insecticides against novel molecular targets in order to circumvent resistance mechanisms.Members of the beta-scorpion toxin family display an extraordinary species-selective toxicity towards insects. beta-toxins bind with voltage-gated sodium channels but the binding determinants of the beta-toxin receptor site remain to be fully elucidated. In particular the residues which underpin the species-selectivity of toxin binding are not determined yet.I propose to elucidate the binding interactions of the insect-specific BmK IT1 beta-scorpion toxin with its receptor site on the extracellular linkers of the insect domain II voltage-sensor. I plan to use a recently-developed chimeric strategy in a combinatory mutagenesis, electrophysiology and 3D modelling approach in order to generate a description of toxin binding.I have expertise in molecular biology, computer modelling and ion channel expression. To complete my skill set as an ion channel researcher, I require practical electrophysiology experience. With this grant, I will pursue three goals: 1. Training in electrophysiology techniques. 2. Application of these techniques to study BmK IT1 binding with insect receptor site and thereby answering three questions: a: Which sodium channel function is modified by BmK IT1? b: Where on the voltage-sensor paddle does BmK IT bind? c: Does the insect S1-S2 linker modify BmK IT binding? The third goal is to develop a 3D molecular model of BmK IT interaction with the insect receptor site, thereby providing valuable structural information to enable pharmacophore modelling aiding novel insecticide design.