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Structural insights into the South African HIV-1 subtype C protease: impact of hinge region dynamics and flap flexibility in drug resistance
Faculty
Pharmacy
Year:
2013
Type of Publication:
Article
Pages:
1370-1380
Authors:
Naicker, Previn, Achilonu, Ikechukwu, Fanucchi, Sylvia, Fernandes, Manuel, Ibrahim, Mahmoud A. A, Dirr, Heini W, Soliman, Mahmoud E. S, Sayed, Yasien
DOI:
10.1080/07391102.2012.736774
Journal:
JOURNAL OF BIOMOLECULAR STRUCTURE \& DYNAMICS TAYLOR \& FRANCIS INC
Volume:
31
Research Area:
Biochemistry \& Molecular Biology; Biophysics
ISSN
ISI:000326014900002
Keywords :
HIV-1 protease, South African subtype C, hinge region, salt bridge, flap region, flexibility, crystal structure, molecular dynamics
Abstract:
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 angstrom, 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.An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:36
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