This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Prabu-Jeyabalan, M.
Right arrow Articles by Schiffer, C. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Prabu-Jeyabalan, M.
Right arrow Articles by Schiffer, C. A.

 Previous Article  |  Next Article 

Journal of Virology, January 2003, p. 1306-1315, Vol. 77, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.2.1306-1315.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Viability of a Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variant: Structural Insights for Better Antiviral Therapy

Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Nancy M. King, and Celia A. Schiffer*

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Received 28 May 2002/ Accepted 11 October 2002

Under the selective pressure of protease inhibitor therapy, patients infected with human immunodeficiency virus (HIV) often develop drug-resistant HIV strains. One of the first drug-resistant mutations to arise in the protease, particularly in patients receiving indinavir or ritonavir treatment, is V82A, which compromises the binding of these and other inhibitors but allows the virus to remain viable. To probe this drug resistance, we solved the crystal structures of three natural substrates and two commercial drugs in complex with an inactive drug-resistant mutant (D25N/V82A) HIV-1 protease. Through structural analysis and comparison of the protein-ligand interactions, we found that Val82 interacts more closely with the drugs than with the natural substrate peptides. The V82A mutation compromises these interactions with the drugs while not greatly affecting the substrate interactions, which is consistent with previously published kinetic data. Coupled with our earlier observations, these findings suggest that future inhibitor design may reduce the probability of the appearance of drug-resistant mutations by targeting residues that are essential for substrate recognition.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St. (LRB), Worcester, MA 01605. Phone: (508) 856-8008. Fax: (508) 856-6464. E-mail: Celia.Schiffer{at}umassmed.edu.

Journal of Virology, January 2003, p. 1306-1315, Vol. 77, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.2.1306-1315.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Foulkes, J. E., Prabu-Jeyabalan, M., Cooper, D., Henderson, G. J., Harris, J., Swanstrom, R., Schiffer, C. A. (2006). Role of Invariant Thr80 in Human Immunodeficiency Virus Type 1 Protease Structure, Function, and Viral Infectivity. J. Virol. 80: 6906-6916 [Abstract] [Full Text]  
  • Prabu-Jeyabalan, M., King, N. M., Nalivaika, E. A., Heilek-Snyder, G., Cammack, N., Schiffer, C. A. (2006). Substrate Envelope and Drug Resistance: Crystal Structure of RO1 in Complex with Wild-Type Human Immunodeficiency Virus Type 1 Protease. Antimicrob. Agents Chemother. 50: 1518-1521 [Abstract] [Full Text]  
  • Prabu-Jeyabalan, M., Nalivaika, E. A., Romano, K., Schiffer, C. A. (2006). Mechanism of Substrate Recognition by Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variants Revealed by a Novel Structural Intermediate. J. Virol. 80: 3607-3616 [Abstract] [Full Text]  
  • Bouchonnet, F., Dam, E., Mammano, F., de Soultrait, V., Hennere, G., Benech, H., Clavel, F., Hance, A. J. (2005). Quantification of the Effects on Viral DNA Synthesis of Reverse Transcriptase Mutations Conferring Human Immunodeficiency Virus Type 1 Resistance to Nucleoside Analogues. J. Virol. 79: 812-822 [Abstract] [Full Text]  
  • Prabu-Jeyabalan, M., Nalivaika, E. A., King, N. M., Schiffer, C. A. (2004). Structural Basis for Coevolution of a Human Immunodeficiency Virus Type 1 Nucleocapsid-p1 Cleavage Site with a V82A Drug-Resistant Mutation in Viral Protease. J. Virol. 78: 12446-12454 [Abstract] [Full Text]  
  • King, N. M., Prabu-Jeyabalan, M., Nalivaika, E. A., Wigerinck, P., de Bethune, M.-P., Schiffer, C. A. (2004). Structural and Thermodynamic Basis for the Binding of TMC114, a Next-Generation Human Immunodeficiency Virus Type 1 Protease Inhibitor. J. Virol. 78: 12012-12021 [Abstract] [Full Text]  
  • Charpentier, C., Dwyer, D. E., Mammano, F., Lecossier, D., Clavel, F., Hance, A. J. (2004). Role of Minority Populations of Human Immunodeficiency Virus Type 1 in the Evolution of Viral Resistance to Protease Inhibitors. J. Virol. 78: 4234-4247 [Abstract] [Full Text]  
  • Logsdon, B. C., Vickrey, J. F., Martin, P., Proteasa, G., Koepke, J. I., Terlecky, S. R., Wawrzak, Z., Winters, M. A., Merigan, T. C., Kovari, L. C. (2004). Crystal Structures of a Multidrug-Resistant Human Immunodeficiency Virus Type 1 Protease Reveal an Expanded Active-Site Cavity. J. Virol. 78: 3123-3132 [Abstract] [Full Text]  


Copyright © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»