Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of Witwatersrand, Johannesburg, 2050, South Africa; School of Chemistry, University of Witwatersrand, Johannesburg, 2050, South Africa; School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom; Faculty of Science, Department of Chemistry, Minia University, Minia, 61519, Egypt; School of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa; Faculty of Pharmacy, Department of Pharmaceutical Organic Chemistry, Zagazig University, Zagazig, 44519, Egypt
Naicker, P., Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of Witwatersrand, Johannesburg, 2050, South Africa; Achilonu, I., Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of Witwatersrand, Johannesburg, 2050, South Africa; Fanucchi, S., Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of Witwatersrand, Johannesburg, 2050, South Africa; Fernandes, M., School of Chemistry, University of Witwatersrand, Johannesburg, 2050, South Africa; Ibrahim, M.A.A., School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom, Faculty of Science, Department of Chemistry, Minia University, Minia, 61519, Egypt; Dirr, H.W., Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of Witwatersrand, Johannesburg, 2050, South Africa; Soliman, M.E.S., School of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa, Faculty of Pharmacy, Department of Pharmaceutical Organic Chemistry, Zagazig University, Zagazig, 44519, Egypt; Sayed, Y., Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of Witwatersrand, Johannesburg, 2050, South Africa
The HIV protease plays a major role in the life cycle of the virus and has long been a target in antiviral therapy. Resistance of HIV protease to protease inhibitors (PIs) is problematic for the effective treatment of HIV infection. The South African HIV-1 subtype C protease (C-SA PR), which contains eight polymorphisms relative to the consensus HIV-1 subtype B protease, was expressed in Escherichia coli, purified, and crystallized. The crystal structure of the C-SA PR was resolved at 2.7 Å, which is the first crystal structure of a HIV-1 subtype C protease that predominates in Africa. Structural analyses of the C-SA PR in comparison to HIV-1 subtype B proteases indicated that polymorphisms at position 36 of the homodimeric HIV-1 protease may impact on the stability of the hinge region of the protease, and hence the dynamics of the flap region. Molecular dynamics simulations showed that the flap region of the C-SA PR displays a wider range of movements over time as compared to the subtype B proteases. Reduced stability in the hinge region resulting from the absent E35-R57 salt bridge in the C-SA PR, most likely contributes to the increased flexibility of the flaps which may be associated with reduced susceptibility to PIs. © 2013 Taylor & Francis.
Human immunodeficiency virus 1 subtype C protease; Human immunodeficiency virus proteinase; proteinase inhibitor; unclassified drug; antiviral resistance; antiviral susceptibility; article; consensus; controlled study; crystal structure; crystallization; enzyme purification; enzyme stability; enzyme structure; Escherichia coli; Human immunodeficiency virus 1; molecular dynamics; nonhuman; priority journal; protein expression; protein polymorphism; simulation; South Africa; structure analysis; Amino Acid Sequence; Catalytic Domain; Crystallography, X-Ray; Drug Resistance, Viral; Enzyme Stability; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Models, Molecular; Molecular Dynamics Simulation; Molecular Sequence Data; Polymorphism, Genetic; Protein Multimerization; Protein Structure, Secondary; Protein Structure, Tertiary; Sequence Homology, Amino Acid; South Africa
