Effects of mutations in the polymerase domain on the polymerase, RNase H and strand transfer activities of human immunodeficiency virus type 1 reverse transcriptase

Journal of Molecular Biology
H Q GaoS H Hughes

Abstract

Based on structural analyses and on the behavior of mutants, we suggest that the polymerase domain of HIV-1 reverse transcriptase (RT) plays a critical role in holding and appropriately positioning the template-primer both at the polymerase active site and at the RNase H active site. For RT to successfully copy the viral RNA genome, RNase H must cleave the RNA with absolute precision. We believe that a combination of the structure of the template-primer and its precise positioning are responsible for the specific cleavages RNase H makes. We have proposed that resistance of HIV-1 RT to nucleoside analogs involves a subtle repositioning of the template-primer. This hypothesis is based on both structural and biochemical analyses. Mutations that confer resistance to nucleoside analogs do not cluster at the polymerase active site; however, they are in positions where they could alter the interaction between RT and the template-primer. If, as we have hypothesized, the polymerase domain is primarily responsible for positioning the template-primer and RNase H cleavage depends on this positioning, it should be possible to use RNase H cleavage to monitor at least some of the major changes in the position of the template-primer. We have u...Continue Reading

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Citations

Mar 17, 2004·AIDS Research and Human Retroviruses·Maria G IsaguliantsBritta Wahren
Oct 25, 2008·Nucleic Acids Research·Na LiAndrew D Ellington
Apr 1, 2010·Viruses·Greg L Beilhartz, Matthias Götte
Mar 12, 2004·The Journal of Biological Chemistry·Robert A SmithBradley D Preston
Feb 21, 2009·The FEBS Journal·James J Champoux, Sharon J Schultz
Jan 1, 2000·Journal of Biomolecular Structure & Dynamics·R L JerniganD T Flatow
Jul 3, 2004·The Journal of Biological Chemistry·Louise Z WangKenneth A Johnson

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