A multi-drug resistant HIV-1 protease is resistant to the dimerization inhibitory activity of TLF-PafF.
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ABSTRACT: Human immunodeficiency virus type-1 (HIV-1) protease, a homodimeric aspartyl protease, is a critical drug target in designing anti-retroviral drugs to treat HIV/AIDS. Multidrug-resistant (MDR) clinical isolate-769 HIV-1 protease (PDB ID: 3PJ6) has been shown to exhibit expanded active site cavity with wide-open conformation of flaps (Gly48-Gly52) due to the accumulation of multiple mutations. In this study, an HIV-1 protease dimerization inhibitor (PDI)-TLF-PafF, was evaluated against MDR769 HIV-1 protease using X-ray crystallography. It was hypothesized that co-crystallization of MDR769 HIV-1 protease in complex with TLF-PafF would yield either a monomeric or a disrupted dimeric structure. However, crystal structure of MDR769 I10V HIV-1 protease co-crystallized with TLF-PafF revealed an undisrupted dimeric protease structure (PDB ID: 4NKK) that is comparable to the crystal structure of its corresponding apo-protease (PDB ID: 3PJ6). In order to understand the binding profile of TLF-PafF as a PDI, docking analysis was performed using monomeric protease (prepared from the dimeric crystal structure, PDB ID: 4NKK) as docking receptor. Docking analysis revealed that TLF-PafF binds at the N and C termini (dimerization domain) in a clamp shape for the monomeric wild type receptor but not the MDR769 monomeric receptor. TLF-PafF preferentially showed higher binding affinity to the expanded active site cavity of MDR769 HIV-1 protease than to the termini. Irrespective of binding location, the binding affinity of TLF-PafF against wild type receptor (-6.7kcal/mol) was found to be higher compared to its corresponding binding affinity against MDR receptor (-4.6kcal/mol) suggesting that the MDR769 HIV-1 protease could be resistant to the PDI-activity of TLF-PafF, thus supporting the dimeric crystal structure (PDB ID: 4NKK).
SUBMITTER: Yedidi RS
PROVIDER: S-EPMC4287366 | biostudies-literature | 2014 Sep
REPOSITORIES: biostudies-literature
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