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 Å resolution

Journal of Molecular Biology

Volumn 284, Issue 4, 1998, Pages 1095-1111

  Ding, Jianping ^a   Das, Kalyan ^a   Hsiou, Yu ^a   Sarafianos, Stefan G ^a   Clark Jr , Arthur D ^a   Jacobo Molina, Alfredo ^a,c   Tantillo, Chris ^a   Hughes, Stephen H ^b   Arnold, Edward ^a  

^a RUTGERS UNIVERSITY   (United States)

^b NATIONAL CANCER INSTITUTE   (United States)

^c SCHOOL OF ENGINEERING AND SCIENCES   (Mexico)

Author keywords

AIDS; Polymerase active site; Polymerase structure; Protein nucleic acid interaction; X ray crystallography

Indexed keywords

DOUBLE STRANDED DNA; ESSENTIAL AMINO ACID; IMMUNOGLOBULIN F(AB) FRAGMENT; MONOCLONAL ANTIBODY; NUCLEIC ACID; PRIMER DNA; RNA DIRECTED DNA POLYMERASE;

ARTICLE; DRUG INHIBITION; ENZYME ACTIVE SITE; ENZYME STRUCTURE; HUMAN IMMUNODEFICIENCY VIRUS 1; HYDROGEN BOND; NONHUMAN; POLYMERIZATION; PRIORITY JOURNAL; PROTEIN DNA BINDING; PROTEIN STRUCTURE;

HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 0032509101     PISSN: 00222836     EISSN: None     Source Type: Journal    
DOI: 10.1006/jmbi.1998.2208     Document Type: Article

References (92)

1. Argos P. A sequence motif in many polymerases. Nucl. Acids Res. 16:1988;9909-9916.
2. Arnold E., Jacobo-Molina A., Nanni R. G., Williams R. L., Lu X., Ding J., Clark A. D. Jr, Zhang A., Ferris A. L., Clark P., Hizi A., Hughes S. H. Structure of HIV-1 reverse transcriptase/DNA complex at 7 Å resolution showing active site locations. Nature. 357:1992;85-89.
3. Arnold E., Das K., Ding J., Yadav P. N. S., Hsiou Y., Boyer P. L., Hughes S. H. Targeting HIV reverse transcriptase for anti-AIDS drug design. Drug Des. Discov. 13:1996;29-47.
4. Arts E. J., Le Grice S. F. Interaction of retroviral reverse transcriptase with template-primer duplexes during replication. Prog. Nucl. Acid Res. Mol. Biol. 58:1998;339-393.
5. Bakhanashvili M., Avidan O., Hizi A. Mutational studies of human immunodeficiency virus type 1 reverse transcriptase: the involvement of residues 183 and 184 in the fidelity of DNA synthesis. FEBS Letters. 391:1996;257-262.
6. Beard W. A., Stahl S. J., Kim H.-R., Bebenek K., Kumar A., Strub M.-P., Becerra S. P., Kunkel T. A., Wilson S. H. Structure/function studies of human immunodeficiency virus type 1 reverse transcriptase: alanine scanning mutagenesis of an α-helix in the thumb subdomain. J. Biol. Chem. 269:1994;28091-28097.
7. Bebenek K., Beard W. A., Casas-Finet J. R., Kim H.-R., Darden T. A., Wilson S. H., Kunkel T. A. Reduced frameshift fidelity and processivity of HIV-1 reverse transcriptase mutants containing alanine substitutions in helix H of the thumb subdomain. J. Biol. Chem. 270:1995;19516-19523.
8. Bebenek K., Beard W. A., Darden T. A., Li L., Prasad R., Luxon B. A., Gorenstein D. G., Wilson S. H., Kunkel T. A. A minor groove binding track in reverse transcriptase. Nature Struct. Biol. 4:1997;194-197.
9. Boyer P. L., Ferris A. L., Hughes S. H. Cassette mutagenesis of the reverse transcriptase of human immunodeficiency virus type 1. J. Virol. 66:1992;1031-1039.
10. Boyer P., Gao H.-Q., Hughes S. H. A mutation at position 190 of HIV-1 RT interacts with mutations at positions 74 and 75 via the template-primer. Antimicrob. Agents Chemother. 42:1998;447-452.
11. Brunger A. T. The free R value: a novel statistical quantity for assessing the accuracy of crystal structures. Nature. 355:1992;472-474.
12. Brunger A. T. X-PLOR Manual Version 3.1: A System for X-ray Crystallography and NMR. 1993;Yale University Press, New Haven.
13. Burley S. K., Petsko G. A. Aromatic-aromatic interaction: a mechanism of protein structure stabilization. Science. 229:1985;23-28.
14. Carson M. Ribbon models of macromolecules. J. Mol. Graph. 5:1987;103-106.
15. Cavert W., Notermans D. W., Staskus K., Wietgrefe S. W., Zupancic M., Gebhard K., Henry K., Zhang Z. Q., Mills R., McDade H., Goudsmit J., Danner S. A., Haase A. T. Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science. 276:1997;960-964.
16. Chao S.-F., Chan V. L., Juranka P., Kaplan A. H., Swanstrom R., Hutchison C. A. III. Mutational sensitivity patterns define critical residues in the palm subdomain of the reverse transcriptase of human immunodeficiency virus type 1. Nucl. Acids Res. 23:1995;803-810.
17. Clark A. D. Jr, Jacobo-Molina A., Clark P., Hughes S. H., Arnold E. Crystallization of human immunodeficiency virus type 1 reverse transcriptase with and without nucleic acid substrates, inhibitors and an antibody Fab fragment. Methods Enzymol. 262:1995;171-185.
18. Cowtan K. dmmulti. Joint CCP4 and ESF-EACBM Newsletter on Protein Crystallography. 1994;. p. 34-38.
19. Das K., Ding J., Hsiou Y., Clark A. D. Jr, Moereels H., Koymans L., Andries K., Pauwels R., Janssen P. A. J., Boyer P. L., Clark P., Smith R. H. Jr, Kroeger Smith M. B., Michejda C. J., Hughes S. H., Arnold E. Crystal structures of 8-Cl and 9-Cl TIBO complexed with wild-type HIV-1 RT and 8-Cl TIBO complexed with the Tyr181Cys HIV-1 RT drug-resistant mutant. J. Mol. Biol. 264:1996;1085-1100.
20. De Clercq E. HIV resistance to reverse transcriptase inhibitors. Biochem. Pharmacol. 47:1994;155-169.
21. De Clercq E. Antiviral therapy of human immunodeficiency virus infections. Clin. Microbiol. Rev. 8:1995;200-239.
22. De Clercq E. In search of a selective antiviral chemotherapy. Clin. Microbiol. Rev. 10:1997;674-693.
23. Delarue M., Poch O., Tordo N., Moras D., Argos P. An attempt to unify the structure of polymerases. Protein Eng. 6:1990;461-467.
24. Ding J., Arnold E. Using MIRmodelmask procedure to improve the map interpretability and reduce model bias in the structure determination of HIV-1 RT/DNA/Fab complex. Bailey S., Hubbard R., Waller D. From First Map to Final Model. 1994;95-102 SERC Daresbury Laboratory, Daresbury.
25. Ding J., Das K., Moereels H., Koymans L., Andries K., Janssen P. A. J., Hughes S. H., Arnold E. Structure of HIV-1 RT/TIBO R 86183 reveals similarity in the binding of diverse nonnucleoside inhibitors. Nature Struct. Biol. 2:1995a;407-415.
26. Ding J., Das K., Tantillo C., Zhang W., Clark A. D. Jr, Jessen S., Lu X., Hsiou Y., Jacobo-Molina A., Andries K., Pauwels R., Moereels H., Koymans L., Janssen P. A. J., Smith R. et al. Structure of HIV-1 reverse transcriptase in a complex with the nonnucleoside inhibitor α-APA R 95845 at 2.8 Å resolution. Structure. 3:1995b;365-379.
27. Ding J., Das K., Yadav P. N. S., Hsiou Y., Zhang W., Hughes S. H., Arnold E. A review of HIV-1 RT structural studies and implications for drug design. Veerapandian P. Structure Based Drug Design. 1997a;41-82 Marcel Dekker, Inc. New York.
28. Ding J., Hughes S. H., Arnold E. 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. Biopolymers. 44:1997b;125-138.
29. Doublié S., Tabor S., Long A. M., Richardson C. C., Ellenberger T. Crystal structure of a bacteriophage T7 DNA replication complex at 2.2 Å resolution. Nature. 391:1998;251-258.
30. Emini E. A., Fan H. Y. Immunological and pharmacological approaches to the control of retroviral infections. Coffin J. M., Hughes S. H., Varmus H. E. Retroviruses. 1997;637-706 Cold Spring Harbor Laboratory Press, Plainview.
31. Esnouf R., Ren J., Ross C., Jones Y., Stammers D., Stuart D. Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors. Nature Struct. Biol. 2:1995;303-308.
32. Esnouf R., Ren J., Hopkins A., Ross C., Jones E., Stammers D., Stuart D. Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor. Proc. Natl Acad. Sci. USA. 94:1997;3984-3989.
33. Gao Q., Gu Z., Parniak M. A., Cameron J., Cammack N., Boucher C., Wainberg M. A. 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. Antimicrob. Agents Chemother. 37:1993;1390-1392.
34. Gao H. Q., Boyer P. L., Arnold E., Hughes S. H. Effects of mutations in the polymerase domain on the polymerase, RNase H and strand transfer activities of human immunodeficiency virus type 1 reverse transcriptase. J. Mol. Biol. 277:1998;559-572.
35. Georgiadis M. M., Jessen S. M., Ogata C. M., Telesnitsky A., Goff S. P., Hendrickson W. A. Mechanistic implications from the structure of a catalytic fragment of Moloney murine leukemia virus reverse transcriptase. Structure. 3:1995;879-892.
36. Ghosh M., Jacques P. S., Rodgers D. R., Ottman M., Darlix J.-L., Le Grice S. F. Alterations to the primer grip of p66 HIV-1 reverse transcriptase and their consequences for template-primer utilization. Biochemistry. 35:1996;8553-8562.
37. Gu Z., Gao Q., Li X., Parniak M. A., Wainberg M. A. Novel mutation in the human immunodeficiency virus type 1 reverse transcriptase gene that encodes cross-resistance to 2′,3′-dideoxyinosine and 2′,3′-dideoxycytidine. J. Virol. 66:1992;7128-7135.
38. Guajardo R., Sousa R. A model for the mechanism of polymerase translocation. J. Mol. Biol. 265:1997;8-19.
39. Hamlin R. Multiwire area X-ray diffractometers. Methods Enzymol. 114:1985;416-452.
40. Hansen J. L., Long A. M., Schultz S. C. Structure of the RNA-dependent RNA polymerase of poliovirus. Structure. 5:1997;1109-1122.
41. Hopkins A. L., Ren J., Esnouf R. M., Willcox B. E., Jones E. Y., Ross C., Miyasaka T., Walker R. T., Tanaka H., Stammers D. K., Stuart D. I. Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors. J. Med. Chem. 39:1996;1589-1600.
42. Hostomsky Z., Hostomska Z., Fu T.-B., Taylor J. The reverse transcriptase of HIV-1: functionality of the subunits of the heterodimer in DNA synthesis. J. Virol. 66:1992;3179-3182.
43. Howard A. J., Nielsen C., Xuong N. H. Software for a diffractometer with multiwire area detector. Methods Enzymol. 114:1985;452-472.
44. Hsiou Y., Ding J., Das K., Clark A. D. Jr, Hughes S. H., Arnold E. Structure of unliganded HIV-1 reverse transcriptase at 2.7 Å resolution: implications of conformational changes for polymerization and inhibition mechanisms. Structure. 4:1996;853-860.
45. Hunter C. A., Singh J., Thornton J. M. π-π interactions: the geometry and energetics of phenylalanine-phenylalanine interactions in proteins. J. Mol. Biol. 218:1991;837-846.
46. Jacobo-Molina A., Arnold E. HIV reverse transcriptase structure-function relationships. Biochemistry. 30:1991;6351-6361.
47. Jacobo-Molina A., Clark A. D. Jr, Williams R. L., Nanni R. G., Clark P., Ferris A. L., Hughes S. H., Arnold E. Crystals of a ternary complex of human immunodeficiency virus type 1 reverse transcriptase with a monoclonal antibody Fab fragment and double-stranded DNA diffract X-rays to 3.5 Å resolution. Proc. Natl Acad. Sci. USA. 88:1991;10895-10899.
48. Jacobo-Molina A., Ding J., Nanni R. G., Clark A. D. Jr, Lu X., Tantillo C., Williams R. L., Kamer G., Ferris A. L., Clark P., Hizi A., Hughes S. H., Arnold E. Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 Å resolution shows bent DNA. Proc. Natl Acad. Sci. USA. 90:1993;6320-6324.
49. Jacques P. S., Wohrl B. M., Ottmann M., Darlix J. L., Le Grice S. F. J. Mutating the "primer grip" of p66 HIV-1 reverse transcriptase implicates tryptophan-229 in template-primer utilization. J. Biol. Chem. 269:1994;26472-26478.
50. Johnson M. S., McClure M. A., Feng D., Gray J., Doolittle R. F. Computer analysis of retroviral pol genes: assignment of enzymatic functions to specific sequences and homologies with nonviral enzymes. Proc. Natl Acad. Sci. USA. 83:1986;7648-7652.
51. Jones T. A., Zou J. Y., Cowan S. W., Kjeldgaard M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallog. sect. A. 47:1991;110-119.
52. Kamer G., Argos P. Primary structural comparison of RNA-dependent polymerases from plant, animal, and bacterial viruses. Nucl. Acids Res. 12:1984;7269-7282.
53. Kaushik N., Rege N., Yadav P. N., Sarafianos S. G., Modak M. J. Biochemical analysis of catalytically crucial aspartate mutants of human immunodeficiency virus type 1 reverse transcriptase. Biochemistry. 35:1996;11536-11546.
54. Kew Y., Salomon H., Olsen L. R., Wainberg M. A., Prased V. R. The nucleoside analog-resistant E89G mutant of HIV-1 reverse transcriptase displays a broader cross-resistance that extends to nonnucleoside inhibitors. Antimicrob. Agents Chemother. 40:1996;1711-1714.
55. Kiefer J. R., Mao C., Hansen C. J., Basehore S. L., Hogrefe H. H., Braman J. C., Beese L. S. Crystal structure of a thermostable Bacillus DNA polymerase I large fragment at 2.1 Å resolution. Structure. 5:1997;95-108.
56. Kleim J.-P., Roesner M., Winkler I., Paessens A., Kirsch R., Hsiou Y., Arnold E., Riess G. Selective pressure of a quinoxaline class nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT inhibitor specific (RT L74→V/I, V75→L/I) HIV-1 mutants. Proc. Natl Acad. Sci. USA. 93:1996;34-38.
57. Kleywegt G. J., Jones T. A. Halloween, masks and bones. Bailey S., Hubbard R., Waller D. From First Map to Final Model. 1994;59-66 SERC Daresbury Laboratory, Daresbury.
58. Kohlstaedt L. A., Wang J., Friedman J. M., Rice P. A., Steitz T. A. Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science. 256:1992;1783-1790.
59. Larder B. A. Inhibitors of HIV reverse transcriptase as antiviral agents and drug resistance. Skalka A. M., Goff S. P. Reverse Transcriptase. 1993;205-222 Cold Spring Harbor Laboratory Press, Plainview, NY.
60. Larder B. A., Purifoy D. J. M., Powell K. L., Darby G. Site-specific mutagenesis of AIDS virus reverse transcriptase. Nature. 327:1987;716-717.
61. Larder B., A. G., Kemp S. D., Purifoy D. J. M. Infectious potential of human immunodeficiency virus type 1 reverse transcriptase mutants with altered inhibitor sensitivity. Proc. Natl Acad. Sci. USA. 86:1989;4803-4807.
62. Larder B. A., Kemp S. D., Harrigan P. R. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science. 269:1995;696-699.
63. Laskowski R. A., MacArthur M. W., Moss D. S., Thornton J. M. PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Crystallog. 26:1993;283-291.
64. Le Grice S. F. J., Naas T., Wohlgensinger B., Schatz O. Subunit-selective mutagenesis indicates minimal polymerase activity in heterodimer-associated p51 HIV-1 reverse transcriptase. EMBO J. 10:1991;3905-3911.
65. Luzzati V. Traitement statistique des erreurs dans la determination des structures cristallines. Acta Crystallog. 5:1952;802-810.
66. Matthews B. W. Solvent content of protein crystals. J. Mol. Biol. 33:1968;491-497.
67. Minor W. XDISPLAY Program. 1993;Purdue University, Wisconsin.
68. Otwinowski Z., Minor W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276:1996;55-62.
69. Palaniappan C., Wisniewski M., Jacques P. S., Le Grice S. F., Fay P. J., Bambara R. A. Mutations within the primer grip region of HIV-1 reverse transcriptase result in loss of RNase H function. J. Biol. Chem. 272:1997;11157-11164.
70. Patel P. H., Jacobo-Molina A., Ding J., Tantillo C., Clark A. D. Jr, Raag R., Nanni R. G., Hughes S. H., Arnold E. Insights into DNA polymerization mechanisms from structure and function analysis of HIV-1 reverse transcriptase. Biochemistry. 34:1995;5351-5363.
71. Pelletier H., Sawaya M. R., Kumar A., Wilson S. H., Kraut J. Structures of ternary complexes of rat DNA polymerase β, a DNA template-primer, and ddCTP. Science. 264:1994;1891-1903.
72. Pelletier H., Sawaya M. R., Wolfle W., Wilson S. H., Kraut J. Crystal structures of human DNA polymerase β complexed with DNA: implications for catalytic mechanism, processivity, and fidelity. Biochemistry. 35:1996;12742-12761.
73. Perelson A. S., Essunger P., Cao Y., Vesanen M., Hurley A., Saksela K., Markowitz M., Ho D. D. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature. 387:1997;188-191.
74. Poch O., Sauvaget I., Delarue M., Tordo N. Identification of four conserved motifs among the RNA-dependent polymerase encoding elements. EMBO J. 8:1989;3867-3874.
75. Ren J., Esnouf R., Garman E., Somers D., Ross C., Kirby I., Keeling J., Darby G., Jones Y., Stuart D., Stammers D. High resolution structures of HIV-1 RT from four RT-inhibitor complexes. Nature Struct. Biol. 2:1995a;293-302.
76. Ren J., Esnouf R., Hopkins A., Ross C., Jones Y., Stammers D., Stuart D. The structure of HIV-1 reverse transcriptase complexed with 9-chloro-TIBO: lessons for inhibitor design. Structure. 3:1995b;915-926.
77. Rittinger K., Divita G., Goody R. Human immunodeficiency virus reverse transcriptase substrate-induced conformational changes and the mechanism of inhibition by nonnucleoside inhibitors. Proc. Natl Acad. Sci. USA. 92:1995;8046-8049.
78. Rodgers D. W. Cryocrystallography. Structure. 2:1994;1135-1140.
79. Rodgers D. W., Gamblin S. J., Harris B. A., Ray S., Culp J. S., Hellmig B., Woolf D. J., Debouck C., Harrison S. C. The structure of unliganded reverse transcriptase from the human immunodeficiency virus type 1. Proc. Natl Acad. Sci. USA. 92:1995;1222-1226.
80. Sarafianos S. G., Das K., Ding J., Hsiou Y., Hughes S. H., Arnold E. Current perspectives on mechanisms of HIV-1 reverse transcriptase inhibition by nonnucleoside inhibitors. Bentley P. H., O'Hanlon P. J. Anti-Infectives: Recent Advances in Chemistry and Structure Activity Relationships. 1997;328-334 The Royal Society of Chemistry, Cambridge.
81. Schinazi R. F., Lloyd R. J. J., Nguyen M.-H., Cannon D. L., McMillan N., Ilksoy N., Chu C. K., Liotta D. C., Bazmi H. Z., Mellors J. W. Characterization of human immunodeficiency virus resistant to oxathiolane-cytosine nucleosides. Antimicrob. Agents Chemother. 37:1993;875-881.
82. Smerdon S. J., Jager J., Wang J., Kohlstaedt L. A., Chirino A. J., Friedman J. M., Rice P. A., Steitz T. A. Structure of the binding site for nonnucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. Proc. Natl Acad. Sci. USA. 91:1994;3911-3915.
83. Smith M. B. K., Rouzer C. A., Taneyhill L. A., Smith N. A., Hughes S. H., Boyer P. L., Janssen P. A. J., Moereels H., Koymans L., Arnold E., Ding J., Das K., Zhang W., Michejda C. J., Smith R. H. Jr. Molecular modeling studies of HIV-1 reverse transcriptase nonnucleoside inhibitors: total energy of complexation as a predictor of drug placement and activity. Protein Sci. 4:1995;2203-2222.
84. Spence R. A., Kati W. M., Anderson K. S., Johnson K. A. Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science. 267:1995;988-993.
85. Spence R. A., Anderson K. S., Johnson K. A. HIV-1 reverse transcriptase resistance to nonnucleoside inhibitors. Biochemistry. 35:1996;1054-1063.
86. Tantillo C., Ding J., Jacobo-Molina A., Nanni R. G., Boyer P. L., Hughes S. H., Pauwels R., Andries K., Janssen P. A. J., Arnold E. Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase: implications for mechanisms of drug inhibition and resistance. J. Mol. Biol. 243:1994;369-387.
87. Telesnitsky A., Goff S. P. Reverse transcription and the generation of retroviral DNA. Coffin J., Hughes S. H., Varmus H. Retroviruses. 1997;121-160 Cold Spring Harbor Press, Cold Spring Harbor.
88. Teng T. Y. Mounting of crystals for macromolecular crystallography in a free-standing thin film. J. Appl. Crystallog. 24:1990;387-391.
89. Tisdale M., Kemp S. D., Parry N. R., Larder B. A. 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. Proc. Natl Acad. Sci. USA. 90:1993;5653-5656.
90. Wang B. C. Resolution of phase ambiguity in macromolecular crystallography. Methods Enzymol. 115:1985;90-112.
91. Whitcomb J. M., Hughes S. H. Retroviral reverse transcription and integration: progress and problems. Annu. Rev. Cell Biol. 8:1992;275-306.
92. Xiong Y., Eickbush T. H. Origin and evolution of retroelements based upon their reverse transcriptase sequences. EMBO J. 9:1990;3353-3362.