Home > Publications database > A Strategically Located Arg/Lys Residue Promotes Correct Base Paring During Nucleic Acid Biosynthesis in Polymerases > print

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024 7 _ |a 10.1021/jacs.7b12446
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245 _ _ |a A Strategically Located Arg/Lys Residue Promotes Correct Base Paring During Nucleic Acid Biosynthesis in Polymerases
260 _ _ |a Washington, DC
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|b American Chemical Society
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520 _ _ |a Polymerases (Pols) synthesize the double-stranded nucleic acids in the Watson–Crick (W–C) conformation, which is critical for DNA and RNA functioning. Yet, the molecular basis to catalyze the W–C base pairing during Pol-mediated nucleic acids biosynthesis remains unclear. Here, through bioinformatics analyses on a large data set of Pol/DNA structures, we first describe the conserved presence of one positively charged residue (Lys or Arg), which is similarly located near the enzymatic two-metal active site, always interacting directly with the incoming substrate (d)NTP. Incidentally, we noted that some Pol/DNA structures showing the alternative Hoogsteen base pairing were often solved with this specific residue either mutated, displaced, or missing. We then used quantum and classical simulations coupled to free-energy calculations to illustrate how, in human DNA Pol-η, the conserved Arg61 favors W–C base pairing through defined interactions with the incoming nucleotide. Taken together, these structural observations and computational results suggest a structural framework in which this specific residue is critical for stabilizing the incoming (d)NTP nucleotide and base pairing during Pol-mediated nucleic acid biosynthesis. These results may benefit enzyme engineering for nucleic acid processing and encourage new drug discovery strategies to modulate Pols function.
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700 1 _ |a Carloni, Paolo
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700 1 _ |a De Vivo, Marco
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773 _ _ |a 10.1021/jacs.7b12446
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