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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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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
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Drug Resistance Mutations in the Nucleotide Binding Pocket of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Differentially Affect the Phosphorolysis-Dependent Primer Unblocking Activity in the Presence of Stavudine and Zidovudine and Its Inhibition by Efavirenz.
E. Crespan, G. A. Locatelli, R. Cancio, U. Hubscher, S. Spadari, and G. Maga (2005)
Antimicrob. Agents Chemother. 49, 342-349
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Crystal Structure of Complete Rhinovirus RNA Polymerase Suggests Front Loading of Protein Primer.
T. C. Appleby, H. Luecke, J. H. Shim, J. Z. Wu, I. W. Cheney, W. Zhong, L. Vogeley, Z. Hong, and N. Yao (2005)
J. Virol. 79, 277-288
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Mutations in the RNase H Primer Grip Domain of Murine Leukemia Virus Reverse Transcriptase Decrease Efficiency and Accuracy of Plus-Strand DNA Transfer.
J. L. Mbisa, G. N. Nikolenko, and V. K. Pathak (2005)
J. Virol. 79, 419-427
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Domain structure and three-dimensional model of a group II intron-encoded reverse transcriptase.
F. J.H. BLOCKER, G. MOHR, L. H. CONLAN, L. QI, M. BELFORT, and A. M. LAMBOWITZ (2005)
RNA 11, 14-28
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Closing of the Fingers Domain Generates Motor Forces in the HIV Reverse Transcriptase.
H. Lu, J. Macosko, D. Habel-Rodriguez, R. W. Keller, J. A. Brozik, and D. J. Keller (2004)
J. Biol. Chem. 279, 54529-54532
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Requirements for DNA Unpairing during Displacement Synthesis by HIV-1 Reverse Transcriptase.
J. Winshell, B. A. Paulson, B. D. Buelow, and J. J. Champoux (2004)
J. Biol. Chem. 279, 52924-52933
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