title: A multi-drug resistant HIV-1 protease is resistant to the dimerization inhibitory activity of TLF-PafF.
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).
authors.affiliation: Queensborough Community College-City University of New York, Bayside, NY 11364, USA.
authors.forename: Ravikiran S
authors.initials: RS
authors.lastname: Yedidi
authors.affiliation: Queensborough Community College-City University of New York, Bayside, NY 11364, USA.
authors.forename: Gheorghe
authors.initials: G
authors.lastname: Proteasa
authors.affiliation: Queensborough Community College-City University of New York, Bayside, NY 11364, USA.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Martin
authors.affiliation: Queensborough Community College-City University of New York, Bayside, NY 11364, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Queensborough Community College-City University of New York, Bayside, NY 11364, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Vickrey
authors.affiliation: Queensborough Community College-City University of New York, Bayside, NY 11364, USA.
authors.forename: Iulia A
authors.initials: IA
authors.lastname: Kovari
authors.affiliation: Queensborough Community College-City University of New York, Bayside, NY 11364, USA. Electronic address: kovari@med.wayne.edu.
authors.forename: Ladislau C
authors.initials: LC
authors.lastname: Kovari
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D024921:Drug Resistance, Multiple, Viral; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology*; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000737:chemistry*; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; C000598523:TLF-PafF peptide; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1
keywords: Dimerization inhibitors; Docking; HIV-1 protease; HIV/AIDS; TLF-PafF; X-ray crystallography
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