2RKF

HIV-1 PR resistant mutant + LPV


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.194 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Ninety-nine is not enough: molecular characterization of inhibitor-resistant human immunodeficiency virus type 1 protease mutants with insertions in the flap region

Kozisek, M.Saskova, K.G.Rezacova, P.Brynda, J.van Maarseveen, N.M.De Jong, D.Boucher, C.A.Kagan, R.M.Nijhuis, M.Konvalinka, J.

(2008) J Virol 82: 5869-5878

  • DOI: https://doi.org/10.1128/JVI.02325-07
  • Primary Citation of Related Structures:  
    2RKF, 2RKG

  • PubMed Abstract: 

    While the selection of amino acid insertions in human immunodeficiency virus (HIV) reverse transcriptase (RT) is a known mechanism of resistance against RT inhibitors, very few reports on the selection of insertions in the protease (PR) coding region have been published. It is still unclear whether these insertions impact protease inhibitor (PI) resistance and/or viral replication capacity. We show that the prevalence of insertions, especially between amino acids 30 to 41 of HIV type 1 (HIV-1) PR, has increased in recent years. We identified amino acid insertions at positions 33 and 35 of the PR of HIV-1-infected patients who had undergone prolonged treatment with PIs, and we characterized the contribution of these insertions to viral resistance. We prepared the corresponding mutated, recombinant PR variants with or without insertions at positions 33 and 35 and characterized them in terms of enzyme kinetics and crystal structures. We also engineered the corresponding recombinant viruses and analyzed the PR susceptibility and replication capacity by recombinant virus assay. Both in vitro methods confirmed that the amino acid insertions at positions 33 and 35 contribute to the viral resistance to most of the tested PIs. The structural analysis revealed local structural rearrangements in the flap region and in the substrate binding pockets. The enlargement of the PR substrate binding site together with impaired flap dynamics could account for the weaker inhibitor binding by the insertion mutants. Amino acid insertions in the vicinity of the binding cleft therefore represent a novel mechanism of HIV resistance development.


  • Organizational Affiliation

    Gilead Sciences and IOCB Research Center, Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, v.v.i., Flemingovo 2, 166 10 Praha 6, Czech Republic.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PROTEASE RETROPEPSIN
A, B
99Human immunodeficiency virus 1Mutation(s): 8 
Gene Names: gag-pol
EC: 3.4.23.16
UniProt
Find proteins for Q90JJ9 (Human immunodeficiency virus 1)
Explore Q90JJ9 
Go to UniProtKB:  Q90JJ9
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ90JJ9
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
AB1 PDBBind:  2RKF Ki: 0.83 (nM) from 1 assay(s)
BindingDB:  2RKF Ki: 5.00e-3 (nM) from 1 assay(s)
Binding MOAD:  2RKF Ki: 0.83 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.194 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 61.961α = 90
b = 61.961β = 90
c = 84.106γ = 120
Software Package:
Software NamePurpose
HKL-3000data collection
MOLREPphasing
REFMACrefinement
HKL-3000data reduction
HKL-3000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-08-05
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2021-10-20
    Changes: Database references, Derived calculations, Structure summary
  • Version 1.3: 2023-08-30
    Changes: Data collection, Refinement description