Journal
NATURE
Volume 533, Issue 7601, Pages 58-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/nature17938
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Funding
- National Institutes of Health/National Institute of Biomedical Imaging and Bioengineering [R01EB022376]
- DARPA [HR0011-11-2-0003, N66001-12-C-4207]
- Howard Hughes Medical Institute
- US Department of Agriculture National Institute of Food and Agriculture and Agricultural Research Service Biotechnology Risk Assessment [2012-33522-19791]
- Harvard Chemical Biology Program
- National Science Foundation Graduate Research Fellowship
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The Bacillus thuringiensis d-endotoxins (Bt toxins) are widely used insecticidal proteins in engineered crops that provide agricultural, economic, and environmental benefits. The development of insect resistance to Bt toxins endangers their long-term effectiveness. Here we have developed a phage-assisted continuous evolution selection that rapidly evolves high-affinity protein-protein interactions, and applied this system to evolve variants of the Bt toxin Cry1Ac that bind a cadherin-like receptor from the insect pest Trichoplusia ni (TnCAD) that is not natively bound by wild-type Cry1Ac. The resulting evolved Cry1Ac variants bind TnCAD with high affinity (dissociation constant K-d = 11-41 nM), kill TnCAD-expressing insect cells that are not susceptible to wild-type Cry1Ac, and kill Cry1Ac-resistant T. ni insects up to 335-fold more potently than wild-type Cry1Ac. Our findings establish that the evolution of Bt toxins with novel insect cell receptor affinity can overcome insect Bt toxin resistance and confer lethality approaching that of the wild-type Bt toxin against non-resistant insects.
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