Subunit specificity of mutations that confer resistance to nonnucleoside inhibitors in human immunodeficiency virus type 1 reverse transcriptase.

Antimicrobial Agents and Chemotherapy
P L BoyerS H Hughes

Abstract

We constructed plasmid vectors that simultaneously express both the p66 and p51 subunits of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) in Escherichia coli. These vectors allow us to generate HIV-1 RT heterodimers in which either the p66 or the p51 subunit has the wild-type sequence and the other subunit has a specific amino acid substitution. We used these vectors to express HIV-1 RT heterodimers containing several different amino acid substitutions reported to confer resistance to nonnucleoside inhibitors. Most of the amino acid substitutions conferred resistance to nonnucleoside inhibitors R86183 (TIBO) and TSAO-m3T only when present in the p66 subunit of the p66-p51 heterodimer; heterodimers that contained a wild-type p66 subunit and a mutant p51 subunit remained sensitive to the inhibitors. However, there was one mutation, E138K, that conferred drug resistance when the mutation was present in the p51 subunit. The corresponding heterodimer with the E138K mutation in the p66 subunit and a wild-type p51 subunit remained sensitive to the inhibitors. Analysis of the three-dimensional structure of HIV-1 RT indicated that residue 138 of the p51 subunit is in the nonnucleoside inhibitor-binding pocket wh...Continue Reading

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Citations

Feb 10, 2004·Protein Expression and Purification·Esther W HouSamuel H Wilson
Jul 1, 1996·Nature Structural Biology·P L Boyer, S H Hughes
Sep 30, 2010·The Journal of Biological Chemistry·Matthew M SchuckmannStefan G Sarafianos
Apr 12, 2008·Nucleosides, Nucleotides & Nucleic Acids·María-Cruz BonacheAna San-Félix
Jan 22, 1998·Proceedings of the National Academy of Sciences of the United States of America·J A WrobelC A Hutchison
Jul 14, 2004·Proceedings of the National Academy of Sciences of the United States of America·Janice D PataThomas A Steitz
Aug 16, 2001·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Lee T. Bacheler
Jul 12, 2005·Antiviral Chemistry & Chemotherapy·María-José CamarasaMaría-Jesús Pérez-Pérez

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