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Viruses 2009, 1(3), 657-677; doi:10.3390/v1030657
Review

Revisiting Plus-Strand DNA Synthesis in Retroviruses and Long Terminal Repeat Retrotransposons: Dynamics of Enzyme: Substrate Interactions

1, 2 and 3,*
1 Department of Chemistry and Biochemistry, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21228, USA 2 Center for Advanced Research in Biotechnology of the University of Maryland Biotechnology Institute and the National Institute of Standards and Technology, 9600 Gudelsky Drive, Rockville, MD 20850, USA 3 HIV Drug Resistance Program, NCI, National Institutes of Health, Frederick, MD 21702-1201, USA
* Author to whom correspondence should be addressed.
Received: 10 September 2009 / Revised: 28 October 2009 / Accepted: 4 November 2009 / Published: 4 November 2009
(This article belongs to the Special Issue Retroviral Enzymes)
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Abstract

Although polypurine tract (PPT)-primed initiation of plus-strand DNA synthesis in retroviruses and LTR-containing retrotransposons can be accurately duplicated, the molecular details underlying this concerted series of events remain largely unknown. Importantly, the PPT 3’ terminus must be accommodated by ribonuclease H (RNase H) and DNA polymerase catalytic centers situated at either terminus of the cognate reverse transcriptase (RT), and in the case of the HIV-1 enzyme, ~70Å apart. Communication between RT and the RNA/DNA hybrid therefore appears necessary to promote these events. The crystal structure of the HIV-1 RT/PPT complex, while informative, positions the RNase H active site several bases pairs from the PPT/U3 junction, and thus provides limited information on cleavage specificity. To fill the gap between biochemical and crystallographic approaches, we review a multidisciplinary approach combining chemical probing, mass spectrometry, NMR spectroscopy and single molecule spectroscopy. Our studies also indicate that nonnucleoside RT inhibitors affect enzyme orientation, suggesting initiation of plus-strand DNA synthesis as a potential therapeutic target.
Keywords: retroviruses; LTR-retrotransposons; polypurine tract; plus strand DNA synthesis; NMR spectroscopy; single molecule spectroscopy; antiviral strategies retroviruses; LTR-retrotransposons; polypurine tract; plus strand DNA synthesis; NMR spectroscopy; single molecule spectroscopy; antiviral strategies
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Fabris, D.; Marino, J.P.; Le Grice, S.F.J. Revisiting Plus-Strand DNA Synthesis in Retroviruses and Long Terminal Repeat Retrotransposons: Dynamics of Enzyme: Substrate Interactions. Viruses 2009, 1, 657-677.

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