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Science 27 November 1998:
Vol. 282. no. 5394, pp. 1669 - 1675
DOI: 10.1126/science.282.5394.1669
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Research Articles

Structure of a Covalently Trapped Catalytic Complex of HIV-1 Reverse Transcriptase: Implications for Drug Resistance

Huifang Huang, * Rajiv Chopra, * Gregory L. Verdine, dagger Stephen C. Harrison dagger

A combinatorial disulfide cross-linking strategy was used to prepare a stalled complex of human immunodeficiency virus-type 1 (HIV-1) reverse transcriptase with a DNA template:primer and a deoxynucleoside triphosphate (dNTP), and the crystal structure of the complex was determined at a resolution of 3.2 angstroms. The presence of a dideoxynucleotide at the 3'-primer terminus allows capture of a state in which the substrates are poised for attack on the dNTP. Conformational changes that accompany formation of the catalytic complex produce distinct clusters of the residues that are altered in viruses resistant to nucleoside analog drugs. The positioning of these residues in the neighborhood of the dNTP helps to resolve some long-standing puzzles about the molecular basis of resistance. The resistance mutations are likely to influence binding or reactivity of the inhibitors, relative to normal dNTPs, and the clustering of the mutations correlates with the chemical structure of the drug.

H. Huang and G. L. Verdine are in the Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. R. Chopra and S. C. Harrison are at the Howard Hughes Medical Institute and Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: verdine{at}glviris.harvard.edu and schadmin{at}crystal.harvard.edu

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Localization, mobility and fidelity of retrotransposed Group II introns in rRNA genes.
L. H. Conlan, M. J. Stanger, K. Ichiyanagi, and M. Belfort (2005)
Nucleic Acids Res. 33, 5262-5270
   Abstract »    Full Text »    PDF »
Human Immunodeficiency Virus Mutagenesis during Antiviral Therapy: Impact of Drug-Resistant Reverse Transcriptase and Nucleoside and Nonnucleoside Reverse Transcriptase Inhibitors on Human Immunodeficiency Virus Type 1 Mutation Frequencies.
R. Chen, M. Yokoyama, H. Sato, C. Reilly, and L. M. Mansky (2005)
J. Virol. 79, 12045-12057
   Abstract »    Full Text »    PDF »
Analysis of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Subunit Structure/Function in the Context of Infectious Virions and Human Target Cells.
A. Mulky and J. C. Kappes (2005)
Antimicrob. Agents Chemother. 49, 3762-3769
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In Vitro Selection and Analysis of Human Immunodeficiency Virus Type 1 Resistant to Derivatives of {beta}-2',3'-Didehydro-2',3'-Dideoxy-5-Fluorocytidine.
J. L. Hammond, U. M. Parikh, D. L. Koontz, S. Schlueter-Wirtz, C. K. Chu, H. Z. Bazmi, R. F. Schinazi, and J. W. Mellors (2005)
Antimicrob. Agents Chemother. 49, 3930-3932
   Abstract »    Full Text »    PDF »
Nucleotide modification at the {gamma}-phosphate leads to the improved fidelity of HIV-1 reverse transcriptase.
B. A. Mulder, S. Anaya, P. Yu, K. W. Lee, A. Nguyen, J. Murphy, R. Willson, J. M. Briggs, X. Gao, and S. H. Hardin (2005)
Nucleic Acids Res. 33, 4865-4873
   Abstract »    Full Text »    PDF »
The Role of Thr139 in the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Sensitivity to (+)-Calanolide A.
J. Auwerx, F. Rodriguez-Barrios, F. Ceccherini-Silberstein, A. San-Felix, S. Velazquez, E. De Clercq, M.-J. Camarasa, C.-F. Perno, F. Gago, and J. Balzarini (2005)
Mol. Pharmacol. 68, 652-659
   Abstract »    Full Text »    PDF »
Interaction of the Ty3 Reverse Transcriptase Thumb Subdomain with Template-Primer.
A. Bibillo, D. Lener, A. Tewari, and S. F. J. Le Grice (2005)
J. Biol. Chem. 280, 30282-30290
   Abstract »    Full Text »    PDF »
High Sequence Conservation of Human Immunodeficiency Virus Type 1 Reverse Transcriptase under Drug Pressure despite the Continuous Appearance of Mutations.
F. Ceccherini-Silberstein, F. Gago, M. Santoro, C. Gori, V. Svicher, F. Rodriguez-Barrios, R. d'Arrigo, M. Ciccozzi, A. Bertoli, A. d. Monforte, et al. (2005)
J. Virol. 79, 10718-10729
   Abstract »    Full Text »    PDF »
Investigation of the DNA-dependent cyclohexenyl nucleic acid polymerization and the cyclohexenyl nucleic acid-dependent DNA polymerization.
V. Kempeneers, M. Renders, M. Froeyen, and P. Herdewijn (2005)
Nucleic Acids Res. 33, 3828-3836
   Abstract »    Full Text »    PDF »
Remote Site Control of an Active Site Fidelity Checkpoint in a Viral RNA-dependent RNA Polymerase.
J. J. Arnold, M. Vignuzzi, J. K. Stone, R. Andino, and C. E. Cameron (2005)
J. Biol. Chem. 280, 25706-25716
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The L74V Mutation in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Counteracts Enhanced Excision of Zidovudine Monophosphate Associated with Thymidine Analog Resistance Mutations.
L. R. Miranda, M. Gotte, and D. R. Kuritzkes (2005)
Antimicrob. Agents Chemother. 49, 2648-2656
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Allosteric Effects of Ligands and Mutations on Poliovirus RNA-Dependent RNA Polymerase.
J. E. Boerner, J. M. Lyle, S. Daijogo, B. L. Semler, S. C. Schultz, K. Kirkegaard, and O. C. Richards (2005)
J. Virol. 79, 7803-7811
   Abstract »    Full Text »    PDF »
Limited development and progression of resistance of HIV-1 to the nucleoside analogue reverse transcriptase inhibitor lamivudine in human primary macrophages.
S. Aquaro, V. Svicher, F. Ceccherini-Silberstein, A. Cenci, F. Marcuccilli, S. Giannella, L. Marcon, R. Calio, J. Balzarini, and C.-F. Perno (2005)
J. Antimicrob. Chemother. 55, 872-878
   Abstract »    Full Text »    PDF »
Investigating HIV-1 Polypurine Tract Geometry via Targeted Insertion of Abasic Lesions in the (-)-DNA Template and (+)-RNA Primer.
H. Y. Yi-Brunozzi and S. F. J. Le Grice (2005)
J. Biol. Chem. 280, 20154-20162
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Crystal Structures of the RNA-dependent RNA Polymerase Genotype 2a of Hepatitis C Virus Reveal Two Conformations and Suggest Mechanisms of Inhibition by Non-nucleoside Inhibitors.
B. K. Biswal, M. M. Cherney, M. Wang, L. Chan, C. G. Yannopoulos, D. Bilimoria, O. Nicolas, J. Bedard, and M. N. G. James (2005)
J. Biol. Chem. 280, 18202-18210
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A Relaxed Discrimination of 2'-O-Methyl-GTP Relative to GTP between de Novo and Elongative RNA Synthesis by the Hepatitis C RNA-dependent RNA Polymerase NS5B.
H. Dutartre, J. Boretto, J. C. Guillemot, and B. Canard (2005)
J. Biol. Chem. 280, 6359-6368
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Mechanism for nucleoside analog-mediated abrogation of HIV-1 replication: Balance between RNase H activity and nucleotide excision.
G. N. Nikolenko, S. Palmer, F. Maldarelli, J. W. Mellors, J. M. Coffin, and V. K. Pathak (2005)
PNAS 102, 2093-2098
   Abstract »    Full Text »    PDF »
Mechanistic Insights into the Suppression of Drug Resistance by Human Immunodeficiency Virus Type 1 Reverse Transcriptase Using {alpha}-Boranophosphate Nucleoside Analogs.
J. Deval, K. Alvarez, B. Selmi, M. Bermond, J. Boretto, C. Guerreiro, L. Mulard, and B. Canard (2005)
J. Biol. Chem. 280, 3838-3846
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Kinetics of Nucleotide Incorporation Opposite DNA Bulky Guanine N2 Adducts by Processive Bacteriophage T7 DNA Polymerase (Exonuclease-) and HIV-1 Reverse Transcriptase.
H. Zang, T. M. Harris, and F. P. Guengerich (2005)
J. Biol. Chem. 280, 1165-1178
   Abstract »    Full Text »    PDF »


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