Journal
NUCLEIC ACIDS RESEARCH
Volume 47, Issue 13, Pages 6973-6983Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkz513
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Funding
- Defense Advanced Research Projects Agency's Folded Non-Natural Polymers with Biological Function Fold F(x) Program [N66001-16-2-4061]
- National Science Foundation [MCB: 1607111]
- undergraduate NIGMS training grant [R25GM055246, T34GM069337]
- DOE [DE-AC02-05CH11231]
- NSF
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Replicative DNA polymerases are highly efficient enzymes that maintain stringent geometric control over shape and orientation of the template and incoming nucleoside triphosphate. In a surprising twist to this paradigm, a naturally occurring bacterial DNA polymerase I member isolated from Geobacillus stearothermophilus (Bst) exhibits an innate ability to reverse transcribe RNA and other synthetic congeners (XNAs) into DNA. This observation raises the interesting question of how a replicative DNA polymerase is able to recognize templates of diverse chemical composition. Here, we present crystal structures of natural Bst DNA polymerase that capture the post-translocated product of DNA synthesis on templates composed entirely of 2'-deoxy-2'-fluoro-beta-D-arabino nucleic acid (FANA) and alpha-L-threofuranosyl nucleic acid (TNA). Analysis of the enzyme active site reveals the importance of structural plasticity as a possible mechanism for XNA-dependent DNA synthesis and provides insights into the construction of variants with improved activity.
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