Researchers at the University of Texas at Dallas (UTD) have been able to establish the direct involvement of the BT-R3 receptor mediating toxicity of the Cry4B toxin in living cells. Dr. Lee Bulla and colleagues at UTD have demonstrated selective toxicity of Bacillus thuringiensis subsp. israelensis Cry4B toxin by way of the protein receptor BT-R3. Cry toxins are made by Bacillus thuringiensis and the toxins carry insecticidal activity by binding to epithelial cells in the midgut of insects that are susceptible to these toxins. In Anopheles gambiae, Cry4B toxin binds to BT-R3 and sets off an internal molecular pathway that activates apoptosis (programed cell death).
UTD researchers were able to determine direct involvement of the BT-R3 receptor in mediating toxicity of the Cry4B toxin in living cells. The BT-R3 receptor was cloned from Anopheles gambiae. The researchers made use of proteomics, genomics and bioinformatics methods that were developed in Bulla’s lab.
Determination of BT-T3 as the active receptor for the Cry4B toxin demonstrates the power of proteomic, genomics and bioinformatics to identify protein receptors such as BT-R3. Finding the right target begins with data mining of archived protein sequences in genomic and proteomic databases. This results in the selection and description of candidate proteins based on their potential to bring about insecticidal action. Targets that are considered likely candidates can be analyzed in silico by docking calculations, molecular dynamics simulations as well as other techniques to assess target interactions with chemically or genetically altered Cry toxins.
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According to Dr. Mohamed Ibrahim (senior author of the paper), “This kind of strategy will facilitate protein design for creation of new customized Cry proteins and peptide mimics that might be more effective than the natural toxins themselves against Anopheles gambiae and other mosquitoes, and, hopefully, less able to bring about insect host resistance.” This is particularly true of malaria control, since there is no effective vaccine and no anti-malarial medications for long-term use. There are a few drugs available that can bring about relief but no preventive measure. Having knowledge of the Cry4B-BT-R3 complex will lead the way to developing custom proteins and peptides to help control the spread of malaria by mosquitoes.