4NKK

Crystal structure of a multi-drug resistant clinical isolate-769 HIV-1 protease variant that is resistant to the dimerization inhibitory activity of TLF-PafF

Summary for 4NKK

• Entry DOI: 10.2210/pdb4nkk/pdb
• Related: 1TW7 3PJ6
• Descriptor: HIV-1 protease (2 entities in total)
• Functional Keywords: hiv, aids, hiv-1 protease, dimerization inhibitors, protease inhibitors, multidrug-resistance, clinical isolate 769, dimer protease, hydrolase
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 1
• Total formula weight: 10725.58

Authors

Yedidi, R.S.,Proteasa, G.,Kovari, L.C. (deposition date: 2013-11-12, release date: 2014-07-09, Last modification date: 2023-09-20)

Primary citation

Yedidi, R.S.,Proteasa, G.,Martin, P.D.,Liu, Z.,Vickrey, J.F.,Kovari, I.A.,Kovari, L.C.
A multi-drug resistant HIV-1 protease is resistant to the dimerization inhibitory activity of TLF-PafF.
J.Mol.Graph.Model., 53C:105-111, 2014

PubMed 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).

PubMed: 25108107
DOI: 10.1016/j.jmgm.2014.06.010

Experimental method

X-RAY DIFFRACTION (1.8 Å)