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000844312 245__ $$aA Strategically Located Arg/Lys Residue Promotes Correct Base Paring During Nucleic Acid Biosynthesis in Polymerases
000844312 260__ $$aWashington, DC$$bAmerican Chemical Society$$c2018
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000844312 520__ $$aPolymerases (Pols) synthesize the double-stranded nucleic acids in the Watson–Crick (W–C) conformation, which is critical for DNA and RNA functioning. Yet, the molecular basis to catalyze the W–C base pairing during Pol-mediated nucleic acids biosynthesis remains unclear. Here, through bioinformatics analyses on a large data set of Pol/DNA structures, we first describe the conserved presence of one positively charged residue (Lys or Arg), which is similarly located near the enzymatic two-metal active site, always interacting directly with the incoming substrate (d)NTP. Incidentally, we noted that some Pol/DNA structures showing the alternative Hoogsteen base pairing were often solved with this specific residue either mutated, displaced, or missing. We then used quantum and classical simulations coupled to free-energy calculations to illustrate how, in human DNA Pol-η, the conserved Arg61 favors W–C base pairing through defined interactions with the incoming nucleotide. Taken together, these structural observations and computational results suggest a structural framework in which this specific residue is critical for stabilizing the incoming (d)NTP nucleotide and base pairing during Pol-mediated nucleic acid biosynthesis. These results may benefit enzyme engineering for nucleic acid processing and encourage new drug discovery strategies to modulate Pols function.
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000844312 7001_ $$0P:(DE-Juel1)145614$$aCarloni, Paolo$$b1$$ufzj
000844312 7001_ $$00000-0003-4022-5661$$aDe Vivo, Marco$$b2$$eCorresponding author
000844312 773__ $$0PERI:(DE-600)1472210-0$$a10.1021/jacs.7b12446$$gVol. 140, no. 9, p. 3312 - 3321$$n9$$p3312 - 3321$$tJournal of the American Chemical Society$$v140$$x1520-5126$$y2018
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