Advertisement

Analysis of Temperature-Sensitive Mutants of the HIV-1 Protease

  • M. Manchester
  • D. D. Loeb
  • L. Everitt
  • M. Moody
  • C. A. HutchisonIII
  • R. Swanstrom
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 306)

Abstract

Human Immunodeficiency Virus Type-1, like other retroviruses, encodes an aspartic proteinase whose activity is required for the production of infectious virions.1–6 The protease (PR) is encoded at the 5′ end of the viral pol gene and is responsible for cleavage of the viral gag and gag/pol precursor proteins to their mature forms.7,8 Viruses with inactivating mutations in their protease domain yield immature, noninfectious particles containing unprocessed gag and gag/pol polyproteins;1 for this reason the enzyme has been a prime target for structural and biochemical studies leading to the design of inhibitors of virus replication.

Keywords

Human Immunodeficiency Virus Human Immunodeficiency Virus Type Aspartic Proteinase Protease Domain Human Immunodeficiency Virus Protease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    N. E. Kohl, E. A. Emini, W. A. Schleif, L. J. Davis, J. C. Heimbach, R. A. Dixon, E. M. Scolnick and I. S. Sigal, Active human immunodeficiency virus protease is required for viral infectivity, Proc. Natl. Acad. Sci. U. S. A. 85: 4686–4690 (1988).PubMedCrossRefGoogle Scholar
  2. 2.
    C. Peng, B. Ho, T. Chang and N. Chang, Role of human immunodeficiency virus type 1 specific protease in core maturation and viral infectivity, J. Virol. 63: 2550–2556 (1989).PubMedGoogle Scholar
  3. 3.
    H. G. Göttlinger, J. G. Sodroski and W. A. Haseltine, Role of capsid precursor processing and myristoylation in morphogenesis and infectivity of the human immunodeficiency virus type 1, Proc. Natl. Acad. Sci. U. S. A. 86: 5781–5785 (1989).PubMedCrossRefGoogle Scholar
  4. 4.
    S. Crawford and S. P. Goff, A deletion mutant in the 5′ part of the pol gene of Moloney murine leukemia virus blocks proteolytic processing of gag and pol polyproteins, J. Virol. 53: 899–907 (1985).PubMedGoogle Scholar
  5. 5.
    I. Katoh, Y. Yoshinaka, A. Rein, M. Shibuya, T. Odaka and S. Orozlan, Murine leukemia virus maturation: protease region required for conversion from “immature” to “mature” core form and for infectivity, Virology 145: 280–292 (1985).PubMedCrossRefGoogle Scholar
  6. 6.
    Von der Helm, K., Cleavage of Rous sarcoma viral polypeptide precursor into internal structural proteins in vitro involves viral protein pl5, Proc. Natl. Acad. Sci. U.S.A. 74: 911–915 (1977).PubMedCrossRefGoogle Scholar
  7. 7.
    S. Oroszlan and R. B. Luftig, Retroviral proteinases, in: “Retroviruses: strategies for replication,” R. Swanstrom and P. K. Vogt, eds., Springer, Berlin, Curr. Top. Microbiol. Immunol. 157: 153–185 (1990).Google Scholar
  8. 8.
    R. Swanstrom, A. Kaplan and M. Manchester, The aspartic proteinase of HIV-1, Seminars in Virology 1: 175–186 (1990).Google Scholar
  9. 9.
    T. D. Meek, B. D. Dayton, B. W. Metcalf, G. B. Dreyer, J. E. Strickler, J. G. Gorniak, M. Rosenberg, M. L. Moore, V. W. Magaard and C. Debouck, Human immunodeficiency virus 1 protease expressed in Escherichia coli behaves as a dimeric aspartic protease, Proc. Natl. Acad. Sci. U. S. A. 86: 1841–1845 (1989).PubMedCrossRefGoogle Scholar
  10. 10.
    I. Katoh, Y. Ikawa and Y. Yoshinaka, Retrovirus protease characterized as a dimeric aspartic proteinase, J. Virol. 63: 2226–2232 (1989).PubMedGoogle Scholar
  11. 11.
    A. Wlodawer, M. Miller, M. Jaskólski, B. K. Sathyanarayana, E. Baldwin, I. T. Weber, L. M. Selk, L. Clawson, J. Schneider and S. B. H. Kent, Conserved folding in retroviral proteases: Crystal structure of a synthetic HIV-1 protease, Science 245: 616–621 (1989).PubMedCrossRefGoogle Scholar
  12. 12.
    M. A. Navia, P. M. Fitzgerald, B. M. McKeever, C.-T. Leu, J. C. Heimbach, W. K. Herber, I. S. Sigal, P. L. Darke and J. P. Springer, Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1, Nature 337: 615–1920 (1989).PubMedCrossRefGoogle Scholar
  13. 13.
    M. Miller, M. Jaskolski, J. K. M. Rao, J. Leis and A. Wlodawer, Crystal structure of a retroviral protease proves relationship to aspartic protease family, Nature 337: 576–579 (1989).PubMedCrossRefGoogle Scholar
  14. 14.
    R. Lapatto, T. Blundell, A. Hemmings, J. Overington, A. Wilderspin S. Wood, J. R. Merson, P. J. Whittle, D. E. Danley, K. F. Geoghegan, S. J. Hawrylik, S. E. Lee, K. G. Scheid and P. M. Hobart, X-ray analysis of HIV-1 proteinase at 2.7 Å resolution confirms structural homology among retroviral enzymes, Nature 342: 299–302 (1989).PubMedCrossRefGoogle Scholar
  15. 15.
    M. Miller, B. K. Sathyanarayana, M. V. Toth, G. R. Marshall, L. Clawson, L. Selk, J. Schneider, S. B. H. Kent and A. Wlodawer, Structure of complex of synthetic HIV-1 protease with a substrate-based inhibitor at 2.3 Å resolution, Science 246: 1149–1152 (1989).PubMedCrossRefGoogle Scholar
  16. 16.
    J. Erickson, D. J. Neidhart, J. Van Drie, D. J. Kampf, X. C. Wang, D. W. Norbeck, J. J. Plattner, J. W. Rittenhouse, M. Turon, N. Wideburg, W. E. Kohlbrenner, R. Simmer, R. Helfrich, D. A. Paul and M. Knigge, Design, activity and 2.8 Å crystal structure of a C2 symmetric inhibitor complexed to HIV-1 protease, Science 249: 527–533 (1990).PubMedCrossRefGoogle Scholar
  17. 17.
    W. G. Farmerie, D. D. Loeb, N. C. Casavant, C. A. Hutchison III, M. H. Edgell and R. Swanstrom, Expression and processing of the AIDS virus reverse transcriptase in Escherichia coli, Science 236: 305–308 (1987).PubMedCrossRefGoogle Scholar
  18. 18.
    D. D. Loeb, C. A. Hutchison, M. H. Edgell, W. G. Farmerie and R. Swanstrom, Mutational analysis of human immunodeficiency virus type 1 protease suggests functional homology with aspartic proteinases, J. Virol. 63: 111–121 (1989).PubMedGoogle Scholar
  19. 19.
    D. D. Loeb, R. Swanstrom, L. Everitt, M. Manchester, S. E. Stamper and C. A. Hutchison, Complete mutagenesis of the HIV-1 protease, Nature 340: 397–400 (1989).PubMedCrossRefGoogle Scholar
  20. 20.
    T. Alber, D.-P. Sun, J. A. Nye, D. C. Muchmore and B. W. Matthews, Temperature-sensitive mutations of bacteriophage T4 lysozyme occur at sites with low mobility and low solvent accessibility in the folded protein, Biochemistry 26: 3754–3758 (1987).PubMedCrossRefGoogle Scholar
  21. 21.
    M. O. Dayhoff, R. M. Schwartz and B. C. Orcut, in: “Atlas of Protein Sequence and Structure,” M. O. Dayhoff, ed., 5: 345–352 (1978).Google Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • M. Manchester
    • 1
    • 4
  • D. D. Loeb
    • 2
    • 4
  • L. Everitt
    • 2
    • 4
  • M. Moody
    • 2
    • 4
  • C. A. HutchisonIII
    • 3
    • 4
  • R. Swanstrom
    • 2
    • 4
  1. 1.Curriculum in GeneticsUniversity of North Carolina at Chapel HillChapel HillUSA
  2. 2.Department of BiochemistryUniversity of North Carolina at Chapel HillChapel HillUSA
  3. 3.Department of Microbiology and ImmunologyUniversity of North Carolina at Chapel HillChapel HillUSA
  4. 4.Lineberger Cancer Research CenterUniversity of North Carolina at Chapel HillChapel HillUSA

Personalised recommendations