title: Nucleotide Sugar Pucker Preference Mitigates Excision by HIV-1 RT.
abstract: A series of DNA primers containing nucleotides with various sugar pucker conformations at the 3'-terminus were chemically synthesized by solid-phase synthesis. The ability of wild-type (WT) HIV-1 reverse transcriptase (RT) and AZT-resistant (AZTr) RT to excise the 3'-terminal nucleotide was assessed. Nucleosides with a preference for the North conformation were more refractory to excision by both WT-RT and AZTr-RT. We found that DNA primers that contain North puckered-nucleotides at the 3'-terminus can also affect the translocation status of the RT/template/primer complex, which provides an underlying mechanism to avoid being excised. Together, these results point to a correlation between the sugar conformation of the 3'-terminal nucleotide, the precise position of HIV-1 RT on its nucleic acid substrate, and, in turn, its catalytic function. Nucleotide sugar conformation is therefore an important parameter in defining the susceptibility to RT-catalyzed phosphorolytic excision.
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada.
authors.forename: Ken
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Wahba
authors.affiliation: Department of Biochemistry, McGill University , 3655 Sir William Osler Promenade, Montreal, Quebec H3G1Y6, Canada.
authors.forename: Jean A
authors.initials: JA
authors.lastname: Bernatchez
authors.affiliation: Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh , 450 Technology Drive, Pittsburgh, Pennsylvania 15219-3143, United States.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ilina
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada.
authors.forename: Saúl
authors.initials: S
authors.lastname: Martínez-Montero
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada.
authors.forename: Maryam
authors.initials: M
authors.lastname: Habibian
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada.
authors.forename: Glen F
authors.initials: GF
authors.lastname: Deleavey
authors.affiliation: Department of Biochemistry, McGill University , 3655 Sir William Osler Promenade, Montreal, Quebec H3G1Y6, Canada.|Department of Microbiology and Immunology, McGill University , 3775 University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Matthias
authors.initials: M
authors.lastname: Götte
authors.affiliation: Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh , 450 Technology Drive, Pittsburgh, Pennsylvania 15219-3143, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Parniak
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada.
authors.forename: Masad J
authors.initials: MJ
authors.lastname: Damha
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D009705:Nucleosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D060327:Solid-Phase Synthesis Techniques; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D009705:Nucleosides; D015215:Zidovudine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase