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J Am Chem Soc. 2016 Apr 27;138(16):5194-7. doi: 10.1021/jacs.6b01023. Epub 2016 Apr 18.

In Vivo Biosynthesis of a β-Amino Acid-Containing Protein.

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Department of Chemistry, ‡Department of Molecular, Cellular, and Developmental Biology, and §Department of Molecular Biophysics and Biochemistry, Yale University , New Haven, Connecticut 06520-8107, United States.


It has recently been reported that ribosomes from erythromycin-resistant Escherichia coli strains, when isolated in S30 extracts and incubated with chemically mis-acylated tRNA, can incorporate certain β-amino acids into full length DHFR in vitro. Here we report that wild-type E. coli EF-Tu and phenylalanyl-tRNA synthetase collaborate with these mutant ribosomes and others to incorporate β(3)-Phe analogs into full length DHFR in vivo. E. coli harboring the most active mutant ribosomes are robust, with a doubling time only 14% longer than wild-type. These results reveal the unexpected tolerance of E. coli and its translation machinery to the β(3)-amino acid backbone and should embolden in vivo selections for orthogonal translational machinery components that incorporate diverse β-amino acids into proteins and peptides. E. coli harboring mutant ribosomes may possess the capacity to incorporate many non-natural, non-α-amino acids into proteins and other sequence-programmed polymeric materials.

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