scholarly journals Efavirenz Binding Site in HIV-1 Reverse Transcriptase Monomers

Biochemistry ◽  
2010 ◽  
Vol 49 (49) ◽  
pp. 10565-10573 ◽  
Author(s):  
Valerie A. Braz ◽  
Mary D. Barkley ◽  
Rebecca A. Jockusch ◽  
Patrick L. Wintrode
Keyword(s):  
Reverse Transcriptase ◽  
Binding Site ◽  
Hiv 1

All-Atom Models for the Non-Nucleoside Binding Site of HIV-1 Reverse Transcriptase Complexed with Inhibitors:  A 3D QSAR Approach†

1996 ◽  
Vol 39 (8) ◽  
pp. 1645-1650 ◽  
Author(s):  
Rick Gussio ◽  
Nagarajan Pattabiraman ◽  
Daniel W. Zaharevitz ◽  
Glen E. Kellogg ◽  
Igor A. Topol ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Binding Site ◽  
3D Qsar ◽  
Hiv 1

scholarly journals Theoretical studies of energetics and binding isotope effects of binding a triazole-based inhibitor to HIV-1 reverse transcriptase

2016 ◽  
Vol 18 (1) ◽  
pp. 310-317 ◽  
Author(s):  
A. Krzemińska ◽  
K. P. Świderek ◽  
P. Paneth
Keyword(s):  
Reverse Transcriptase ◽  
Binding Site ◽  
Isotope Effect ◽  
Isotope Effects ◽  
Theoretical Studies ◽  
Hiv 1

The 18O binding isotope effect allows us to distinguish the actual binding site of an inhibitor in HIV-1 reverse transcriptase.

scholarly journals The Phenylmethylthiazolylthiourea Nonnucleoside Reverse Transcriptase (RT) Inhibitor MSK-076 Selects for a Resistance Mutation in the Active Site of Human Immunodeficiency Virus Type 2 RT

2004 ◽  
Vol 78 (14) ◽  
pp. 7427-7437 ◽  
Author(s):  
Joeri Auwerx ◽  
Miguel Stevens ◽  
An R. Van Rompay ◽  
Louise E. Bird ◽  
Jingshan Ren ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Binding Site ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Active Site ◽  
Resistance Mutation ◽  
Site Directed Mutagenesis ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The phenylmethylthiazolylthiourea (PETT) derivative MSK-076 shows, besides high potency against human immunodeficiency virus type 1 (HIV-1), marked activity against HIV-2 (50% effective concentration, 0.63 μM) in cell culture. Time-of-addition experiments pointed to HIV-2 reverse transcriptase (RT) as the target of action of MSK-076. Recombinant HIV-2 RT was inhibited by MSK-076 at 23 μM. As was also found for HIV-1 RT, MSK-076 inhibited HIV-2 RT in a noncompetitive manner with respect to dGTP and poly(rC)·oligo(dG) as the substrate and template-primer, respectively. MSK-076 selected for A101P and G112E mutations in HIV-2 RT and for K101E, Y181C, and G190R mutations in HIV-1 RT. The selected mutated strains of HIV-2 were fully resistant to MSK-076, and the mutant HIV-2 RT enzymes into which the A101P and/or G112E mutation was introduced by site-directed mutagenesis showed more than 50-fold resistance to MSK-076. Mapping of the resistance mutations to the HIV-2 RT structure ascertained that A101P is located at a position equivalent to the nonnucleoside RT inhibitor (NNRTI)-binding site of HIV-1 RT. G112E, however, is distal to the putative NNRTI-binding site in HIV-2 RT but close to the active site, implying a novel molecular mode of action and mechanism of resistance. Our findings have important implications for the development of new NNRTIs with pronounced activity against a wider range of lentiviruses.

scholarly journals Mutations in the U5 Region Adjacent to the Primer Binding Site Affect tRNA Cleavage by Human Immunodeficiency Virus Type 1 Reverse Transcriptase In Vivo

2007 ◽  
Vol 82 (2) ◽  
pp. 719-727 ◽  
Author(s):  
Jangsuk Oh ◽  
Mary Jane McWilliams ◽  
John G. Julias ◽  
Stephen H. Hughes
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Binding Site ◽  
Rnase H ◽  
Primer Binding Site ◽  
Cleavage Specificity ◽  
Immunodeficiency Virus ◽  
Trna Primer ◽  
Hiv 1

ABSTRACT In retroviruses, the first nucleotide added to the tRNA primer defines the end of the U5 region in the right long terminal repeat, and the subsequent removal of this tRNA primer by RNase H exactly defines the U5 end of the linear double-stranded DNA. In most retroviruses, the entire tRNA is removed by RNase H cleavage at the RNA/DNA junction. However, the RNase H domain of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase cleaves the tRNA 1 nucleotide from the RNA/DNA junction at the U5/primer binding site (PBS) junction, which leaves an rA residue at the U5 terminus. We made sequence changes at the end of the U5 region adjacent to the PBS in HIV-1 to determine whether such changes affect the specificity of tRNA primer cleavage by RNase H. In some of the mutants, RNase H usually removed the entire tRNA, showing that the cleavage specificity was shifted by 1 nucleotide. This result suggests that the tRNA cleavage specificity of the HIV-1 RNase domain H depends on sequences in U5.

Exploring the dNTP -binding site of HIV-1 reverse transcriptase for inhibitor design

2021 ◽  
pp. 113785
Author(s):  
Weijie Gu ◽  
Sergio Martinez ◽  
Abhimanyu K. Singh ◽  
Hoai Nguyen ◽  
Jef Rozenski ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Binding Site ◽  
Inhibitor Design ◽  
Dntp Binding ◽  
Hiv 1

scholarly journals Identifying and Characterizing a Functional HIV-1 Reverse Transcriptase-binding Site on Integrase

2009 ◽  
Vol 284 (12) ◽  
pp. 7931-7939 ◽  
Author(s):  
Thomas A. Wilkinson ◽  
Kurt Januszyk ◽  
Martin L. Phillips ◽  
Shewit S. Tekeste ◽  
Min Zhang ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Binding Site ◽  
Hiv 1

scholarly journals A Nucleotide Substitution in the tRNALys Primer Binding Site Dramatically Increases Replication of Recombinant Simian Immunodeficiency Virus Containing a Human Immunodeficiency Virus Type 1 Reverse Transcriptase

2002 ◽  
Vol 76 (11) ◽  
pp. 5803-5806 ◽  
Author(s):  
Kelly Soderberg ◽  
Lynn Denekamp ◽  
Sarah Nikiforow ◽  
Karen Sautter ◽  
Ronald C. Desrosiers ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Binding Site ◽  
Simian Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Nucleotide Substitution ◽  
Primer Binding Site ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT A recombinant simian immunodeficiency virus (SIV) derived from strain 239 (SIVmac239) with reverse transcriptase (RT) sequences from human immunodeficiency virus type 1 (HIV-1) strain HXB2 was severely impaired for replication. Detectable p27Gag levels were not observed until day 65 and peak p27Gag levels were not reached until day 75 after transfection of CEMx174 cells with the recombinant DNA. Sequences from the latter time point did not contain amino acid substitutions in HIV-1 RT; however, a single nucleotide substitution (thymine to cytosine) was found at position eight of the SIV primer binding site. We engineered an RT/SHIV genome with the thymine-to-cytosine substitution, called RT/SHIV/TC, and observed dramatically faster replication kinetics than were observed with the parental RT/SHIV from which this variant was derived. RT/SHIV/TC provides an improved system for study of the impact of drug resistance mutations in HIV-1 RT in a relevant animal model.

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