title: Structural insights into the South African HIV-1 subtype C protease: impact of hinge region dynamics and flap flexibility in drug resistance.
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 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.
authors.affiliation: a Protein Structure-Function Research Unit , School of Molecular and Cell Biology, University of Witwatersrand , Johannesburg , 2050 , South Africa .
authors.forename: Previn
authors.initials: P
authors.lastname: Naicker
authors.forename: Ikechukwu
authors.initials: I
authors.lastname: Achilonu
authors.forename: Sylvia
authors.initials: S
authors.lastname: Fanucchi
authors.forename: Manuel
authors.initials: M
authors.lastname: Fernandes
authors.forename: Mahmoud A A
authors.initials: MA
authors.lastname: Ibrahim
authors.forename: Heini W
authors.initials: HW
authors.lastname: Dirr
authors.forename: Mahmoud E S
authors.initials: ME
authors.lastname: Soliman
authors.forename: Yasien
authors.initials: Y
authors.lastname: Sayed
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics; D004795:Enzyme Stability / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013019:South Africa
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1