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Science 26 June 1992:
Vol. 256. no. 5065, pp. 1783 - 1790
DOI: 10.1126/science.1377403
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Articles

Science, Vol 256, Issue 5065, 1783-1790
Copyright © 1992 by American Association for the Advancement of Science

articles

Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor

LA Kohlstaedt, J Wang, JM Friedman, PA Rice, and TA Steitz

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511.

A 3.5 angstrom resolution electron density map of the HIV-1 reverse transcriptase heterodimer complexed with nevirapine, a drug with potential for treatment of AIDS, reveals an asymmetric dimer. The polymerase (pol) domain of the 66-kilodalton subunit has a large cleft analogous to that of the Klenow fragment of Escherichia coli DNA polymerase I. However, the 51-kilodalton subunit of identical sequence has no such cleft because the four subdomains of the pol domain occupy completely different relative positions. Two of the four pol subdomains appear to be structurally related to subdomains of the Klenow fragment, including one containing the catalytic site. The subdomain that appears likely to bind the template strand at the pol active site has a different structure in the two polymerases. Duplex A-form RNA-DNA hybrid can be model-built into the cleft that runs between the ribonuclease H and pol active sites. Nevirapine is almost completely buried in a pocket near but not overlapping with the pol active site. Residues whose mutation results in drug resistance have been approximately located.


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J. Virol. 77, 1512-1523
   Abstract »    Full Text »    PDF »
Structural Requirements for Potent Anti-Human Immunodeficiency Virus (HIV) and Sperm-Immobilizing Activities of Cyclohexenyl Thiourea and Urea Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase.
O. J. D'Cruz, T. K. Venkatachalam, C. Mao, S. Qazi, and F. M. Uckun (2002)
Biol Reprod 67, 1959-1974
   Abstract »    Full Text »    PDF »
Assembly, purification and crystallization of an active HIV-1 reverse transcriptase initiation complex.
J. D. Pata, B. R. King, and T. A. Steitz (2002)
Nucleic Acids Res. 30, 4855-4863
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Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors.
J. Ren, L. E. Bird, P. P. Chamberlain, G. B. Stewart-Jones, D. I. Stuart, and D. K. Stammers (2002)
PNAS 99, 14410-14415
   Abstract »    Full Text »    PDF »
N4 RNA Polymerase II, a Heterodimeric RNA Polymerase with Homology to the Single-Subunit Family of RNA Polymerases.
S. H. Willis, K. M. Kazmierczak, R. H. Carter, and L. B. Rothman-Denes (2002)
J. Bacteriol. 184, 4952-4961
   Abstract »    Full Text »    PDF »
High Processivity of the Reverse Transcriptase from a Non-long Terminal Repeat Retrotransposon.
A. Bibillo and T. H. Eickbush (2002)
J. Biol. Chem. 277, 34836-34845
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Crystal Structures of Zidovudine- or Lamivudine-Resistant Human Immunodeficiency Virus Type 1 Reverse Transcriptases Containing Mutations at Codons 41, 184, and 215.
P. P. Chamberlain, J. Ren, C. E. Nichols, L. Douglas, J. Lennerstrand, B. A. Larder, D. I. Stuart, and D. K. Stammers (2002)
J. Virol. 76, 10015-10019
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Substrate Requirements for Secondary Cleavage by HIV-1 Reverse Transcriptase RNase H.
M. Wisniewski, Y. Chen, M. Balakrishnan, C. Palaniappan, B. P. Roques, P. J. Fay, and R. A. Bambara (2002)
J. Biol. Chem. 277, 28400-28410
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Destabilization of the HIV-1 Reverse Transcriptase Dimer upon Interaction with N-Acyl Hydrazone Inhibitors.
N. Sluis-Cremer, D. Arion, and M. A. Parniak (2002)
Mol. Pharmacol. 62, 398-405
   Abstract »    Full Text »    PDF »
Mutation of the Catalytic Domain of the Foamy Virus Reverse Transcriptase Leads to Loss of Processivity and Infectivity.
C. S. Rinke, P. L. Boyer, M. D. Sullivan, S. H. Hughes, and M. L. Linial (2002)
J. Virol. 76, 7560-7570
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Substitutions of Phe61 Located in the Vicinity of Template 5'-Overhang Influence Polymerase Fidelity and Nucleoside Analog Sensitivity of HIV-1 Reverse Transcriptase.
T. S. Fisher and V. R. Prasad (2002)
J. Biol. Chem. 277, 22345-22352
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Mechanism of Human Telomerase Inhibition by BIBR1532, a Synthetic, Non-nucleosidic Drug Candidate.
E. Pascolo, C. Wenz, J. Lingner, N. Hauel, H. Priepke, I. Kauffmann, P. Garin-Chesa, W. J. Rettig, K. Damm, and A. Schnapp (2002)
J. Biol. Chem. 277, 15566-15572
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Bacteriophage phi 6 RNA-dependent RNA Polymerase. MOLECULAR DETAILS OF INITIATING NUCLEIC ACID SYNTHESIS WITHOUT PRIMER.
M. R. L. Laurila, E. V. Makeyev, and D. H. Bamford (2002)
J. Biol. Chem. 277, 17117-17124
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Effects of Specific Zidovudine Resistance Mutations and Substrate Structure on Nucleotide-Dependent Primer Unblocking by Human Immunodeficiency Virus Type 1 Reverse Transcriptase.
P. R. Meyer, S. E. Matsuura, A. A. Tolun, I. Pfeifer, A. G. So, J. W. Mellors, and W. A. Scott (2002)
Antimicrob. Agents Chemother. 46, 1540-1545
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Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance.
R. W. Shafer (2002)
Clin. Microbiol. Rev. 15, 247-277
   Abstract »    Full Text »    PDF »
The tRNA Primer Activation Signal in the Human Immunodeficiency Virus Type 1 Genome Is Important for Initiation and Processive Elongation of Reverse Transcription.
N. Beerens and B. Berkhout (2002)
J. Virol. 76, 2329-2339
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