Touching the heart of HIV-1 drug resistance: the fingers close down on the dNTP at the polymerase active site.

Comparison of the recently solved structure of HIV-1 reverse transcriptase (RT)-DNA-dNTP ternary complex with the previously solved structure of RT-DNA binary complex suggests mechanisms by which the HIV-1 RT becomes resistant to nucleoside-analog inhibitors, drugs currently used in the treatment of AIDS.

[1]  T. Steitz,et al.  Structural basis for the 3′‐5′ exonuclease activity of Escherichia coli DNA polymerase I: a two metal ion mechanism. , 1991, The EMBO journal.

[2]  Samuel H. Wilson,et al.  A minor groove binding track in reverse transcriptase , 1997, Nature Structural Biology.

[3]  A. So,et al.  Unblocking of chain-terminated primer by HIV-1 reverse transcriptase through a nucleotide-dependent mechanism. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[4]  T. Kunkel,et al.  Biochemical studies on the reverse transcriptase and RNase H activities from human immunodeficiency virus strains resistant to 3'-azido-3'-deoxythymidine. , 1992, The Journal of biological chemistry.

[5]  M A Wainberg,et al.  Identification of a mutation at codon 65 in the IKKK motif of reverse transcriptase that encodes human immunodeficiency virus resistance to 2',3'-dideoxycytidine and 2',3'-dideoxy-3'-thiacytidine , 1994, Antimicrobial Agents and Chemotherapy.

[6]  S D Kemp,et al.  Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. , 1991, Science.

[7]  S. Sarafianos,et al.  Biochemical analysis of catalytically crucial aspartate mutants of human immunodeficiency virus type 1 reverse transcriptase. , 1996, Biochemistry.

[8]  K A Johnson,et al.  Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors , 1995, Science.

[9]  Yvonne Jones,et al.  Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors , 1995, Nature Structural Biology.

[10]  M. Tsai,et al.  Does the magnesium(II) ion interact with the alpha-phosphate of adenosine triphosphate? An investigation by oxygen-17 nuclear magnetic resonance. , 1982, Biochemistry.

[11]  K. Johnson,et al.  Conformational coupling in DNA polymerase fidelity. , 1993, Annual review of biochemistry.

[12]  E. Arnold,et al.  Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[13]  T. Steitz,et al.  Structure of DNA polymerase I Klenow fragment bound to duplex DNA , 1993, Science.

[14]  D W Rodgers,et al.  The structure of unliganded reverse transcriptase from the human immunodeficiency virus type 1. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Gabriel Waksman,et al.  Crystal structures of open and closed forms of binary and ternary complexes of the large fragment of Thermus aquaticus DNA polymerase I: structural basis for nucleotide incorporation , 1998, The EMBO journal.

[16]  S. Benkovic,et al.  Kinetic mechanism of DNA polymerase I (Klenow). , 1987, Biochemistry.

[17]  James R. Kiefer,et al.  Visualizing DNA replication in a catalytically active Bacillus DNA polymerase crystal , 1998, Nature.

[18]  M. Wainberg,et al.  The same mutation that encodes low-level human immunodeficiency virus type 1 resistance to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine confers high-level resistance to the (-) enantiomer of 2',3'-dideoxy-3'-thiacytidine , 1993, Antimicrobial Agents and Chemotherapy.

[19]  J. Kraut,et al.  Crystal structures of human DNA polymerase beta complexed with DNA: implications for catalytic mechanism, processivity, and fidelity. , 1996, Biochemistry.

[20]  T. Steitz,et al.  Function and structure relationships in DNA polymerases. , 1994, Annual review of biochemistry.

[21]  P. Boyer,et al.  Sensitivity of wild-type human immunodeficiency virus type 1 reverse transcriptase to dideoxynucleotides depends on template length; the sensitivity of drug-resistant mutants does not. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[22]  B. Canard,et al.  Enhanced Binding of Azidothymidine-resistant Human Immunodeficiency Virus 1 Reverse Transcriptase to the 3′-Azido-3′-deoxythymidine 5′-Monophosphate-terminated Primer* , 1998, The Journal of Biological Chemistry.

[23]  Samuel H. Wilson,et al.  Structures of ternary complexes of rat DNA polymerase beta, a DNA template-primer, and ddCTP. , 1994, Science.

[24]  V. Pandey,et al.  Functional Analysis of Amino Acid Residues Constituting the dNTP Binding Pocket of HIV-1 Reverse Transcriptase* , 1998, The Journal of Biological Chemistry.

[25]  Brendan A. Larder,et al.  Site-specific mutagenesis of AIDS virus reverse transcriptase , 1987, Nature.

[26]  S. Sprang,et al.  The structure, catalytic mechanism and regulation of adenylyl cyclase. , 1998, Current opinion in structural biology.

[27]  B. Berkhout,et al.  Initial appearance of the 184Ile variant in lamivudine-treated patients is caused by the mutational bias of human immunodeficiency virus type 1 reverse transcriptase , 1997, Journal of virology.

[28]  Samuel H. Wilson,et al.  Studies on the mechanism of human immunodeficiency virus reverse transcriptase. Steady-state kinetics, processivity, and polynucleotide inhibition. , 1988, The Journal of biological chemistry.

[29]  S. Benkovic,et al.  Kinetic mechanism of DNA polymerase I (Klenow fragment): identification of a second conformational change and evaluation of the internal equilibrium constant. , 1991, Biochemistry.

[30]  D. Stammers,et al.  Closing in on HIV drug resistance , 1999, Nature Structural Biology.

[31]  T. Glonek.  31P NMR of Mg-ATP in dilute solutions: complexation and exchange. , 1992, The International journal of biochemistry.

[32]  S. Thrall,et al.  Single-step kinetics of HIV-1 reverse transcriptase mutants responsible for virus resistance to nucleoside inhibitors zidovudine and 3-TC. , 1997, Biochemistry.

[33]  Jianping Ding,et al.  Protein-nucleic acid interactions and DNA conformation in a complex of human immunodeficiency virus type 1 reverse transcriptase with a double-stranded DNA template-primer. , 1997, Biopolymers.

[34]  G L Verdine,et al.  Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. , 1998, Science.

[35]  S D Kemp,et al.  Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). , 1989, Science.

[36]  K. Anderson,et al.  Mechanism and fidelity of HIV reverse transcriptase. , 1992, The Journal of biological chemistry.

[37]  E. Kool,et al.  Difluorotoluene, a Nonpolar Isostere for Thymine, Codes Specifically and Efficiently for Adenine in DNA Replication. , 1997, Journal of the American Chemical Society.

[38]  S. Sarafianos,et al.  Glutamine 151 participates in the substrate dNTP binding function of HIV-1 reverse transcriptase. , 1995, Biochemistry.

[39]  S D Kemp,et al.  Zidovudine-resistant human immunodeficiency virus selected by passage in cell culture , 1991, Journal of virology.

[40]  R. Schinazi,et al.  Anti-human immunodeficiency virus activities of the beta-L enantiomer of 2',3'-dideoxycytidine and its 5-fluoro derivative in vitro , 1994, Antimicrobial Agents and Chemotherapy.

[41]  Samuel H. Wilson,et al.  Crystal structures of human DNA polymerase beta complexed with gapped and nicked DNA: evidence for an induced fit mechanism. , 1997, Biochemistry.

[42]  L. Loeb,et al.  Human Immunodeficiency Virus Reverse Transcriptase , 1996, The Journal of Biological Chemistry.

[43]  M. Hirsch,et al.  Resistance to 2',3'-dideoxycytidine conferred by a mutation in codon 65 of the human immunodeficiency virus type 1 reverse transcriptase , 1994, Antimicrobial Agents and Chemotherapy.

[44]  A. D. Clark,et al.  Structure of unliganded HIV-1 reverse transcriptase at 2.7 A resolution: implications of conformational changes for polymerization and inhibition mechanisms. , 1996, Structure.

[45]  S D Kemp,et al.  Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3'-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Thomas A. Steitz,et al.  Structure of Taq polymerase with DNA at the polymerase active site , 1996, Nature.

[47]  A. D. Clark,et al.  Structure and functional implications of the polymerase active site region in a complex of HIV-1 RT with a double-stranded DNA template-primer and an antibody Fab fragment at 2.8 A resolution. , 1998, Journal of molecular biology.

[48]  D M Coen,et al.  Molecular mechanisms of antiviral resistance. , 1995, Antiviral research.

[49]  S R Sprang,et al.  Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS. , 1997 .

[50]  R F Schinazi,et al.  Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides , 1993, Antimicrobial Agents and Chemotherapy.

[51]  M. Hillebrand,et al.  Insertion of two amino acids combined with changes in reverse transcriptase containing tyrosine-215 of HIV-1 resistant to multiple nucleoside analogs. , 1999, AIDS.

[52]  P. Boyer,et al.  Mutational analysis of the fingers domain of human immunodeficiency virus type 1 reverse transcriptase , 1992, Journal of virology.

[53]  C L Verlinde,et al.  Structure-based drug design: progress, results and challenges. , 1994, Structure.

[54]  D. Baldwin,et al.  Pulmonary disposition of antimicrobial agents: methodological considerations , 1992, Antimicrobial Agents and Chemotherapy.

[55]  J. Hsieh,et al.  Kinetic mechanism of the DNA-dependent DNA polymerase activity of human immunodeficiency virus reverse transcriptase. , 1993, The Journal of biological chemistry.

[56]  M. Parniak,et al.  Phenotypic mechanism of HIV-1 resistance to 3'-azido-3'-deoxythymidine (AZT): increased polymerization processivity and enhanced sensitivity to pyrophosphate of the mutant viral reverse transcriptase. , 1998, Biochemistry.

[57]  R. Goody,et al.  Human immunodeficiency virus reverse transcriptase substrate-induced conformational changes and the mechanism of inhibition by nonnucleoside inhibitors. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[58]  T. Merigan,et al.  Multidrug-resistant human immunodeficiency virus type 1 strains resulting from combination antiretroviral therapy , 1996, Journal of virology.

[59]  A. D. Clark,et al.  Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 A resolution shows bent DNA. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[60]  S. Doublié,et al.  Crystal structure of a bacteriophage T7 DNA replication complex at 2.2 Å resolution , 1998, Nature.

[61]  E. Arnold,et al.  An in vivo mutation from leucine to tryptophan at position 210 in human immunodeficiency virus type 1 reverse transcriptase contributes to high-level resistance to 3'-azido-3'-deoxythymidine , 1996, Journal of virology.

[62]  M. Wainberg,et al.  K65R mutation of human immunodeficiency virus type 1 reverse transcriptase encodes cross-resistance to 9-(2-phosphonylmethoxyethyl)adenine , 1995, Antimicrobial Agents and Chemotherapy.

[63]  M. Modak,et al.  Significance of the O-helix residues of Escherichia coli DNA polymerase I in DNA synthesis: dynamics of the dNTP binding pocket. , 1996, Biochemistry.

[64]  A. D. Clark,et al.  Insights into DNA polymerization mechanisms from structure and function analysis of HIV-1 reverse transcriptase. , 1995, Biochemistry.

[65]  J. Reardon.  Human immunodeficiency virus reverse transcriptase. A kinetic analysis of RNA-dependent and DNA-dependent DNA polymerization. , 1993, The Journal of biological chemistry.

[66]  D. Katzenstein,et al.  A 6-basepair insert in the reverse transcriptase gene of human immunodeficiency virus type 1 confers resistance to multiple nucleoside inhibitors. , 1998, The Journal of clinical investigation.