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Plasticity and Constraints of tRNA Aminoacylation Define Directed Evolution of Aminoacyl-tRNA Synthetases

1
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA
2
Department of Chemistry, Yale University, New Haven, CT 06520, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(9), 2294; https://doi.org/10.3390/ijms20092294
Received: 15 April 2019 / Revised: 29 April 2019 / Accepted: 7 May 2019 / Published: 9 May 2019
(This article belongs to the Special Issue Expanding and Reprogramming the Genetic Code)
Genetic incorporation of noncanonical amino acids (ncAAs) has become a powerful tool to enhance existing functions or introduce new ones into proteins through expanded chemistry. This technology relies on the process of nonsense suppression, which is made possible by directing aminoacyl-tRNA synthetases (aaRSs) to attach an ncAA onto a cognate suppressor tRNA. However, different mechanisms govern aaRS specificity toward its natural amino acid (AA) substrate and hinder the engineering of aaRSs for applications beyond the incorporation of a single l-α-AA. Directed evolution of aaRSs therefore faces two interlinked challenges: the removal of the affinity for cognate AA and improvement of ncAA acylation. Here we review aspects of AA recognition that directly influence the feasibility and success of aaRS engineering toward d- and β-AAs incorporation into proteins in vivo. Emerging directed evolution methods are described and evaluated on the basis of aaRS active site plasticity and its inherent constraints. View Full-Text
Keywords: aminoacyl-tRNA synthetases; noncanonical amino acids; directed evolution; genetic code expansion; synthetic biology aminoacyl-tRNA synthetases; noncanonical amino acids; directed evolution; genetic code expansion; synthetic biology
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Crnković, A.; Vargas-Rodriguez, O.; Söll, D. Plasticity and Constraints of tRNA Aminoacylation Define Directed Evolution of Aminoacyl-tRNA Synthetases. Int. J. Mol. Sci. 2019, 20, 2294.

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