Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

High resolution structures of HIV-1 RT from four RT–inhibitor complexes

Nature Structural Biology volume 2, pages 293–302 (1995)Cite this article

Abstract

We have determined the structures of four complexes of HIV-1 reverse transcriptase with non-nucleoside inhibitors, three fully refined at high resolution. The highest resolution structure is of the RT-nevirapine complex which has an R-factor of 0.186 and a root-mean-square bond length deviation of 0.015 Å for all data to 2.2 Å. The structures reveal a common mode of binding for these chemically diverse compounds. The common features of binding are largely hydrophobic interactions and arise from induced shape complementarity achieved by conformational rearrangement of the enzyme and conformational/ conf igurational rearrangement of the compounds.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Barre-Sinoussi, F. et al. Isolation of a T-lymphotropic retrovirus from a patient at risk from acquired immunodeficiency syndrome (AIDS). Science 220, 868–871 (1983).

    CAS  PubMed  Google Scholar 

  2. Larder, B.A. & Kemp, S.D. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to Zidovudine (AZT). Science 246, 1155–1158 (1989).

    CAS  PubMed  Google Scholar 

  3. Baba, M. et al. Highly specific inhibition of human immunodeficiency virus type-1 by a novel 6-substituted acyclouridine derivative. biochem. Biophys. Res. Commun. 165, 1375–1381 (1989).

    CAS  PubMed  Google Scholar 

  4. Pauwels, R. et al. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature 343, 470–474 (1990).

    CAS  PubMed  Google Scholar 

  5. Merluzzi, V.J. et al. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science 250, 1411–1413 (1990).

    CAS  PubMed  Google Scholar 

  6. Pauwels, R. et al. Potent and highly selective HIV-1 inhibition by a new series of α-anilino phenyl acetamide (α-APA) derivatives targeted at HIV-1 reverse transcriptase. Proc. natn. Acad. Sci. U.S.A. 90, 1711–1715 (1993).

    CAS  Google Scholar 

  7. Wu, J.C. et al. A novel dipyridodiazepinone inhibitor of HIV-1 reverse transcriptase acts through a non-substrate binding site. Biochemistry 30, 2022–2026 (1991).

    CAS  PubMed  Google Scholar 

  8. Debyser, Z. et al. An antiviral target on reverse transcriptase of human immunodeficiency virus type 1 revealed by tetrahydroimidazo-[4,5 1-jk][1,4]benzodiazepine-2(1H)-one and-thione derivatives. Proc. natn. Acad. Sci. U.S.A. 88, 1451–1455 (1991).

    CAS  Google Scholar 

  9. 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, 1783–1790 (1992).

    CAS  PubMed  Google Scholar 

  10. Richman, D. et al. Human immunodeficiency virus type 1 mutants resistant to non-nucleoside inhibitors of reverse transcriptase arise in tissue culture. Proc. natn. Acad. Sci. U.S.A. 88, 11241–11245 (1991).

    CAS  Google Scholar 

  11. Richman, D.D. et al. Nevirapine resistance mutations of immunodeficiency virus type 1 selected during therapy. J. Virol. 68, 1660–1666 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Larder, B.A. Interactions between drug resistance mutations in human immunodeficiency virus type 1 reverse transcriptase. J. gen. Virol. 75, 951–957 (1994).

    CAS  PubMed  Google Scholar 

  13. De Clercq, E. HIV resistance to reverse transcriptase inhibitors. Biochem. Pharmacol. 47, 155–169 (1994).

    CAS  PubMed  Google Scholar 

  14. Schinazi, R., Larder, B.A. & Mellors, J. Mutations in HIV-1 reverse transcriptase and protease associated with drug resistance. Int. Antiviral News 2, 72–75 (1994).

    Google Scholar 

  15. Jones, E.Y. et al. The growth and characterization of crystals of human immunodeficiency virus (HIV) reverse transcriptase. J. crystal Growth 126, 261–269 (1993).

    CAS  Google Scholar 

  16. Smerdon, S.J. et al. Structureof the binding site for nonnucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. Proc. natn. Acad. Sci. U.S.A. 91, 3911–3915 (1994).

    CAS  Google Scholar 

  17. Jacobo-Molina, A. et al. Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DMA at 3.0 Å resolution shows bent DMA. Proc. natn. Acad. Sci. U.S.A. 90, 6320–6324 (1993).

    CAS  Google Scholar 

  18. Unge, T. et al. 2.2 Å resolution structure of the amino-terminal half of HIV-1 reverse transcriptase (fingers and palm subdomains). Structure 2, 953–961 (1994).

    CAS  PubMed  Google Scholar 

  19. Davies, I.J.F., Hostomska, Z., Hostomsky, Z., Jordan, S.R. & Matthews, D.A. Crystal structure of the Ribonuclease H domain of HIV-1 reverse transcriptase. Science, 252, 88–95 (1991).

    CAS  PubMed  Google Scholar 

  20. Hargrave, K.D. et al. Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 1. Tricyclic pyridobenzo- and dipyridodiaze-pinones. J. med. Chem. 34, 2231–2241 (1991).

    CAS  PubMed  Google Scholar 

  21. Esnouf, R. et al. Mechanism of inhibition of HIV-1 reverse transcriptase by Non-nucleoside Inhibitors. Nature struct. Biol. 2, 303–308 (1995).

    CAS  PubMed  Google Scholar 

  22. Stammers, D.K. et al. Crystals of HIV-1 reverse transcriptase diffracting to 2.2 Å resolution. J. molec. Biol. 242, 586–588 (1994).

    CAS  PubMed  Google Scholar 

  23. Yuasa, S. et al. Selective and synergistic inhibition of human immunodeficiency virus type 1 reverse transcriptase by a non-nucleoside inhibitor, MKC-442. Molec. Pharmacol 44, 895–900 (1993).

    CAS  Google Scholar 

  24. Balzarini, J., Karlsson, A. & De Clercq, E. Human immunodeficiency virus type 1 drug-resistance patterns with different 1-[-hydroxyethoxymethyl]-6-phenylthiothymine derivatives. Molec. Pharmacol. 44, 694–701 (1993).

    CAS  Google Scholar 

  25. Byrnes, V.W. et al. Comprehensive mutant enzyme and viral variant assessment of human immunodeficiency virus type 1 reverse transcriptase resistance to nonnucleoside inhibitors. Antimicrob. Agents Chemother. 37, 1576–1579(1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Balzarini, J. et al. HIV-1 specific reverse transcriptase inhibitors show differential activity against HIV-1 mutant strains containing different amino acid substitutions in the reverse transcriptase. Virology 192, 246–253 (1993).

    CAS  PubMed  Google Scholar 

  27. Balzarini, J. et al. Human immunodeficiency virus 1 (HIV-1)-specific reverse transcriptase (RT) inhibitors may suppress the replication of specific drug-resistant E138K RT HIV-1 mutants or select for highly resistant Y181C—C1811 RT HIV-1 mutants. Proc. natn. Acad. Sci. U.S.A. 91, 6599–6603 (1994).

    CAS  Google Scholar 

  28. Mellors, J.W. et al. Rapid emergence of HIV-1 resistant to nonnucleoside inhibitors of reverse transcriptase. Antiviral Res. 17 S1, 48 (1992).

    Google Scholar 

  29. Sardana, V.V. et al. Functional analysis of HIV-1 reverse transcriptase amino acids involved in resistance to multiple nonnucleoside inhibitors. J. biol.Chem. 267, 17526–17530 (1992).

    CAS  PubMed  Google Scholar 

  30. Dueweke, T.J. et al. A mutation in reverse transcriptase of bisheteroarylpiperazine-resistant human immunodeficiency virus type 1 that confers increased sensitivity to other nonnucleoside inhibitors. Proc. natn. Acad. Sci. U.S.A. 90, 4713–4717 (1993).

    CAS  Google Scholar 

  31. Maass, G. et al. Viral resistance to the thiazolo-iso-indolineones, a new class of nonnucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase. Antimicrob. Agents Chemother. 37, 2612–2617 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Vandamme, A.-M. et al. Characterization of HIV-1 strains isolated from patients treated with TIBO R82913. AIDS Res. hum. Retroviruses 10, 39–46 (1994).

    CAS  PubMed  Google Scholar 

  33. Balzarini, J. et al. Treatment of human immunodeficiency virus type 1 (HIV-1 )-infected cells with combinations of HIV-1-specific inhibitors results in a different resistance pattern than does treatment with single-drug therapy. J. Virol. 67, 5353–5359 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Nunberg, J.H. et al. Viral resistance to human immunodeficiency virus type-1-specific pyridinone reverse transcriptase inhibitors. J. Virol. 65, 4887–4892 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Jacques, P.S., Wohrl, B.M., Howard, K.J. & Le Grice, S.F.J. Modulation of HIV-1 reverse transcriptase function in “selectively deleted” p66/p51 heterodimers. J. biol. Chem. 269, 1388–1393 (1994).

    CAS  PubMed  Google Scholar 

  36. Sakabe, N. X-ray diffraction data collection system for modern protein crystallography with a Weissenberg camera and an imaging plate using synchrotron radiation. Nucl. instr. Methods phys. Res 303, 448–463 (1991).

    Google Scholar 

  37. Stuart, D.I. & Jones, E.Y. Weissenberg data collection for macromolecular crystallography. Curr. Opin. struct. Biol. 3, 737–740 (1993).

    CAS  Google Scholar 

  38. Higashi,T. J. Auto-indexing of oscillation images. J. appl. Crystallogr. 23, 253–257 (1990).

    CAS  Google Scholar 

  39. Otwinowski, Z. Oscillation data reduction program, in Data collection and Processing ( eds. Sawyer, L., Isaacs, N. & Bailey, S.) 56–62 (SERC Daresbury Laboratory, Warrington, England; 1993).

    Google Scholar 

  40. Brunger, A.T. V3.1., X-PLOR Manual. (Yale University, New Haven, CT; 1992).

    Google Scholar 

  41. CCP4. The CCP4 suite: programs for protein crystallography. Acta crystallogr. D50, 760–763 (1994).

  42. Brünger, A.T., Krukowski, A. & Erickson, J. Slow-cooling protocols for crystallographic refinement by simulated annealing. Acta crystallogr. A46, 585–593 (1990).

    Google Scholar 

  43. Jones, T.A. Interactive computer graphics: FRODO. Meths Enzymol. 115, 157–171 (1985).

    CAS  Google Scholar 

  44. Debyser, Z. et al. Allosteric inhibition of human immunodeficiency virus type 1 reverse transcriptase by tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1 H)-one and -thione compounds. Molec. Pharmacol. 41, 203–208 (1992).

    CAS  Google Scholar 

  45. Stuart, D.I., Levine, M., Muirhead, H. & Stammers, D.K. The crystal Structure of cat pyruvate kinase at a resolution of 2. 6 Å. J molec. Biol. 134, 109–142 (1979).

    CAS  PubMed  Google Scholar 

  46. 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 crystallogr. A47, 110–119 (1991).

    CAS  Google Scholar 

  47. Kabsch, W. & Sander, C. Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 22. 2577–2637 (1983).

    CAS  PubMed  Google Scholar 

  48. Kraulis, P.J. MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures. J. appl. Crystallogr. 24, 946–950 (1991).

    Google Scholar 

  49. Merritt, E.A. & Murphy, M.E.P. Raster3D version 2.0. A program for photorealistic molecular graphics. Acta crystallogr. D50, 869–873 (1994).

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Laboratory of Molecular Biophysics, Rex Richards Building, South Parks Road, Oxford, 0X1 3QU, UK

    Jingshan Ren, Robert Esnouf, Elspeth Garman, Yvonne Jones & David Stuart

  2. The Oxford Centre for Molecular Sciences, New Chemistry Building, South Parks Road, Oxford, 0X1 3QT, UK

    Robert Esnouf, Yvonne Jones & David Stuart

  3. Structural Biology Group, Langley Court, Beckenham, Kent, BR3 BBS, UK

    Donald Somers, Carl Ross, Ian Kirby, James Keeling & David Stammers

  4. Biology Division, The Wellcome Research Laboratories, Langley Court, Beckenham, Kent, BR3 BBS, UK

    Graham Darby

Authors
  1. Jingshan Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert Esnouf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elspeth Garman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Donald Somers
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carl Ross
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ian Kirby
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. James Keeling
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Graham Darby
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yvonne Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David Stuart
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. David Stammers
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ren, J., Esnouf, R., Garman, E. et al. High resolution structures of HIV-1 RT from four RT–inhibitor complexes. Nat Struct Mol Biol 2, 293–302 (1995). https://doi.org/10.1038/nsb0495-293

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsb0495-293

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing