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:

Crystal structure of a tethered dimer of HIV-1 proteinase complexed with an inhibitor

Nature Structural Biology volume 1, pages 552–556 (1994)Cite this article

Abstract

HIV-1 proteinase (HIV PR) is a dimeric enzyme composed of two identical polypeptide chains that associate with twofold symmetry. We have determined to 1.8 Å the crystal structure of a covalently tethered dimer of HIV PR. The tethered dimer:inhibitor complex is identical in nearly every respect to the complex of the same inhibitor with the wild type dimeric molecule, except for the linker region. Our results suggest that the tethered dimer may be a useful surrogate enzyme for studying the effects of single site mutations on substrate and inhibitor binding as well as on enzyme asymmetry, and for simulating independent mutational drift of the two domains which has been proposed to have led to the evolution of modern day, single-chain aspartic proteinases.

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. Huff, J.R. HIV protease: a novel chemotherapeutic target for AIDS J. med. Chem. 34, 2305–2314 (1991)

    Article  CAS  PubMed  Google Scholar 

  2. Meek, T.D. Inhibitors of HIV-1 protease J. Enzym. Inhib. 6, 65–98 (1992)

    Article  CAS  PubMed  Google Scholar 

  3. Norbeck, D.W. & Kempf, D.J. HIV protease inhibitors. Ann. Rep. med. Chem. 26, 141–150 (1991)

    CAS  Google Scholar 

  4. Tomasselli, A.G., Howe, W.J., Sawyer, T.K., Wlodawer, A. & Heinrikson, R.L. The complexities of AIDS: an assessment of the HIV protease as a therapeutic target. Chimica Oggi 6–27 (1991)

  5. Erickson, J.W. Design and structure of symmetry-based inhibitors of HIV-1 protease. Perspect. drug dis. Design 1, 109–128(1993)

    Article  CAS  Google Scholar 

  6. Otto, M.J. et al. In vitro isolation and identification of human immunodeficiency virus (HIV) variants with reduced sensitivity to C-2 symmetrical inhibitors of HIV type 1 protease. Proc. natn. Acad. Sci. U.S.A. 90, 7543–7547 (1993)

    Article  CAS  Google Scholar 

  7. Ho, D.D. et al. Characterization of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor. J. Virol. 68, 2016–2020 (1994)

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kaplan, A.H. et al. Selection of HIV-1 variants which encode viral proteases with decreased sensitivity to an inhibitor of the viral protease. Proc. natn. Acad. Sci. USA. (in the press 1994).

  9. Cheng, Y.-S.E., Yin, F.H., Foundling, S., Blomstrom, D. & Kettner, C.A. Stability and activity of human immunodeficiency virus protease: comparison of the natural dimer with a homologous, single-chain tethered dimer. Proc. natn. Acad. Sci. U.S.A. 87, 9660–9664 (1990)

    Article  CAS  Google Scholar 

  10. Dilanni, C.L. et al. Characterization of an active single polypeptide form of the human immunodeficiency virus type 1 protease. J. biol. Chem. 265, 17348–17354 (1990)

    Google Scholar 

  11. Kräusslich, H.-G. Human immunodeficiency virus proteinase dimer as component of the viral polyprotein prevents particle assembly and viral infectivity. Proc. natn. Acad. Sci. U.S.A. 88, 3213–3217 (1991)

    Article  Google Scholar 

  12. Griffiths, J. et al. Interactions of substrates and inhibitors with a family of tethered HIV-1 and HIV-2 Homo- and Heterodimers. J. biol. Chem. 269, 4787–4793 (1994)

    CAS  PubMed  Google Scholar 

  13. Hosur, M.V. et al. Influence of stereochemistry on activity and binding modes for C2 symmetric-based diol inhibitors of HIV-1 protease. J. Am. chem. Soc. 116, 848–855 (1994)

    Article  Google Scholar 

  14. Wlodawer, A. & Erickson, J.W. Structure-based inhibitors of HIV-1 protease.. Rev. Biochem. 62, 543–585 (1993)

    Article  CAS  Google Scholar 

  15. Topol, I.A., Cachau, R.E., Burt, S.K. & Erickson, J.W. in Aspartic Proteinases. (ed. Takahashi, K.) (Plenum Press, New York, 1994).

    Google Scholar 

  16. Rao, J.K.M., Erickson, J.W. & Wlodawer, A. Structural and evolutionary relationships between retroviral and eucaryotic aspartic proteinases. Biochemistry 30, 4663–4671 (1991)

    Article  CAS  PubMed  Google Scholar 

  17. Tang, J. & Wong, R. Evolution in the structure and function of aspartic proteases. J. cell. Biochem. 33, 53–63 (1987)

    Article  CAS  PubMed  Google Scholar 

  18. Kuzmic, P. Kinetic assay for HIV proteinase subunit dissociation. Biochem. biophys. Res. Comm. 191, 998–1003 (1993)

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Structural Biochemistry Program, Frederick Biomedical Supercomputing Center, PRI/DynCorp, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland, 21702-1201, USA

    T. Narayana Bhat, Eric T. Baldwin, Beishan Liu & John W. Erickson

  2. DuPont-Merck Pharmaceutical Co., Wilmington, Delaware, 19880, USA

    Yih-Shyun E. Cheng

Authors
  1. T. Narayana Bhat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric T. Baldwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Beishan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yih-Shyun E. Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John W. Erickson
    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

Bhat, T., Baldwin, E., Liu, B. et al. Crystal structure of a tethered dimer of HIV-1 proteinase complexed with an inhibitor. Nat Struct Mol Biol 1, 552–556 (1994). https://doi.org/10.1038/nsb0894-552

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsb0894-552

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