4GYE

MDR 769 HIV-1 Protease in Complex with Reduced P1F


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.27 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


This is version 3.0 of the entry. See complete history


Literature

Ligand modifications to reduce the relative resistance of multi-drug resistant HIV-1 protease.

Dewdney, T.G.Wang, Y.Liu, Z.Sharma, S.K.Reiter, S.J.Brunzelle, J.S.Kovari, I.A.Woster, P.M.Kovari, L.C.

(2013) Bioorg Med Chem 21: 7430-7434

  • DOI: https://doi.org/10.1016/j.bmc.2013.09.045
  • Primary Citation of Related Structures:  
    4GYE, 4GZF

  • PubMed Abstract: 

    Proper proteolytic processing of the HIV-1 Gag/Pol polyprotein is required for HIV infection and viral replication. This feature has made HIV-1 protease an attractive target for antiretroviral drug design for the treatment of HIV-1 infected patients. To examine the role of the P1 and P1'positions of the substrate in inhibitory efficacy of multi-drug resistant HIV-1 protease 769 (MDR 769), we performed a series of structure-function studies. Using the original CA/p2 cleavage site sequence, we generated heptapeptides containing one reduced peptide bond with an L to F and A to F double mutation at P1 and P1' (F-r-F), and an A to F at P1' (L-r-F) resulting in P1/P1' modified ligands. Here, we present an analysis of co-crystal structures of CA/p2 F-r-F, and CA/p2 L-r-F in complex with MDR 769. To examine conformational changes in the complex structure, molecular dynamic (MD) simulations were performed with MDR769-ligand complexes. MD trajectories show the isobutyl group of both the lopinavir analog and the CA/p2 L-r-F substrate cause a conformational change of in the active site of MDR 769. IC50 measurements suggest the non identical P1/P1' ligands (CA/p2 L-r-F and lopinavir analog) are more effective against MDR proteases as opposed to identical P1/P1'ligands. Our results suggest that a non identical P1/P1'composition may be more favorable for the inhibition of MDR 769 as they induce conformational changes in the active site of the enzyme resulting in disruption of the two-fold symmetry of the protease, thus, stabilizing the inhibitor in the active site.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Biology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protease
A, B
99Human immunodeficiency virus 1Mutation(s): 5 
Gene Names: pol
UniProt
Find proteins for Q9QM22 (Human immunodeficiency virus 1)
Explore Q9QM22 
Go to UniProtKB:  Q9QM22
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9QM22
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
P1F peptide6synthetic constructMutation(s): 0 
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
NLE
Query on NLE
C
L-PEPTIDE LINKINGC6 H13 N O2LEU
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.27 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.255α = 90
b = 62.255β = 90
c = 83.92γ = 120
Software Package:
Software NamePurpose
HKL-2000data collection
REFMACrefinement

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-10-30
    Type: Initial release
  • Version 1.1: 2013-11-13
    Changes: Database references
  • Version 2.0: 2023-02-22
    Changes: Advisory, Atomic model, Data collection, Database references, Derived calculations, Non-polymer description, Polymer sequence, Source and taxonomy, Structure summary
  • Version 2.1: 2023-09-20
    Changes: Data collection, Refinement description
  • Version 3.0: 2023-11-15
    Changes: Atomic model, Data collection