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Gleaning Unexpected Fruits from Hard-Won Synthetases: Probing Principles of Permissivity in Non-canonical Amino Acid–tRNA Synthetases Public Deposited

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This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by John Wiley & Sons, Inc. and can be found at:  http://onlinelibrary.wiley.com/journal/10.1002/%28ISSN%291439-7633

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  • The site-specific incorporation of non-canonical amino acids (ncAAs) into proteins is an important tool for understanding biological function. Traditionally, each new ncAA targeted requires a resource-consuming process of generating new ncAA aminoacyl tRNA synthetase/tRNACUA pairs. However, the discovery that some tRNA synthetases are “permissive,” in that they can incorporate multiple ncAAs, means it is no longer always necessary to develop a new synthetase for each newly desired ncAA. Developing a better understanding of what factors make ncAA-synthetases more permissive would increase the utility of this new approach. Here, we characterize two synthetases selected for the same ncAA that have markedly different “permissivity profiles.” Remarkably, the more permissive synthetase even incorporates an ncAA for which we had not been able to generate a synthetase using de novo selections. Crystal structures reveal that the two synthetases recognize their parent ncAA through a conserved core of interactions, with the more permissive synthetase displaying a greater degree of flexibility in its interaction geometries. We also observe that intra-protein interactions not directly involved in ncAA binding can play a crucial role in synthetase permissivity and suggest that designing such interactions may provide an avenue to engineering synthetases with enhanced permissivity.
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  • Cooley , R. B., Karplus, P. A. and Mehl, R. A. (2014). Gleaning Unexpected Fruits from Hard-Won Synthetases: Probing Principles of Permissivity in Non-canonical Amino Acid-tRNA Synthetases. ChemBioChem, 15(12), 1810-1819. doi:10.1002/cbic.201402180
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  • This work was supported by National Science Foundation (NSF) (grant number MCB-0448297), and services provided by the Cell Imaging and Analysis Facilities and Services Core of the Environmental Health Sciences Center, Oregon State University, were supported by the National Institute of Environmental Health Sciences, National Institutes of Health (grant number P30 ES00210).
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  • description.provenance : Approved for entry into archive by Deanne Bruner(deanne.bruner@oregonstate.edu) on 2014-12-03T19:27:04Z (GMT) No. of bitstreams: 1 MehlRyanBiochemistryBiophysicsGleaningUnexpectedFruits.pdf: 806295 bytes, checksum: e094e1d4c3c8f95110a47c6925cb448d (MD5)
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  • description.provenance : Submitted by Deanne Bruner (deanne.bruner@oregonstate.edu) on 2014-12-03T19:26:18Z No. of bitstreams: 1 MehlRyanBiochemistryBiophysicsGleaningUnexpectedFruits.pdf: 806295 bytes, checksum: e094e1d4c3c8f95110a47c6925cb448d (MD5)

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