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.
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