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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.206 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

A multi-drug resistant HIV-1 protease is resistant to the dimerization inhibitory activity of TLF-PafF.

Yedidi, R.S.Proteasa, G.Martin, P.D.Liu, Z.Vickrey, J.F.Kovari, I.A.Kovari, L.C.

(2014) J Mol Graph Model 53C: 105-111

  • DOI: https://doi.org/10.1016/j.jmgm.2014.06.010
  • Primary Citation of Related Structures:  
    4NKK

  • 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).


  • Organizational Affiliation

    Queensborough Community College-City University of New York, Bayside, NY 11364, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HIV-1 protease99Human immunodeficiency virus 1Mutation(s): 2 
Gene Names: pol
UniProt
Find proteins for Q000H7 (Human immunodeficiency virus 1)
Explore Q000H7 
Go to UniProtKB:  Q000H7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ000H7
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.206 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.875α = 90
b = 44.875β = 90
c = 105.363γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
MOLREPphasing
PHENIXrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-07-09
    Type: Initial release
  • Version 1.1: 2014-08-20
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Refinement description