3D1Y

Crystal structure of HIV-1 mutant I54V and inhibitor SAQUINA


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.05 Å
  • R-Value Free: 0.174 
  • R-Value Work: 0.150 

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This is version 1.4 of the entry. See complete history


Literature

Effect of flap mutations on structure of HIV-1 protease and inhibition by saquinavir and darunavir.

Liu, F.Kovalevsky, A.Y.Tie, Y.Ghosh, A.K.Harrison, R.W.Weber, I.T.

(2008) J Mol Biol 381: 102-115

  • DOI: https://doi.org/10.1016/j.jmb.2008.05.062
  • Primary Citation of Related Structures:  
    3CYW, 3CYX, 3D1X, 3D1Y, 3D1Z, 3D20

  • PubMed Abstract: 

    HIV-1 (human immunodeficiency virus type 1) protease (PR) and its mutants are important antiviral drug targets. The PR flap region is critical for binding substrates or inhibitors and catalytic activity. Hence, mutations of flap residues frequently contribute to reduced susceptibility to PR inhibitors in drug-resistant HIV. Structural and kinetic analyses were used to investigate the role of flap residues Gly48, Ile50, and Ile54 in the development of drug resistance. The crystal structures of flap mutants PR(I50V) (PR with I50V mutation), PR(I54V) (PR with I54V mutation), and PR(I54M) (PR with I54M mutation) complexed with saquinavir (SQV) as well as PR(G48V) (PR with G48V mutation), PR(I54V), and PR(I54M) complexed with darunavir (DRV) were determined at resolutions of 1.05-1.40 A. The PR mutants showed changes in flap conformation, interactions with adjacent residues, inhibitor binding, and the conformation of the 80s loop relative to the wild-type PR. The PR contacts with DRV were closer in PR(G48V)-DRV than in the wild-type PR-DRV, whereas they were longer in PR(I54M)-DRV. The relative inhibition of PR(I54V) and that of PR(I54M) were similar for SQV and DRV. PR(G48V) was about twofold less susceptible to SQV than to DRV, whereas the opposite was observed for PR(I50V). The observed inhibition was in agreement with the association of G48V and I50V with clinical resistance to SQV and DRV, respectively. This analysis of structural and kinetic effects of the mutants will assist in the development of more effective inhibitors for drug-resistant HIV.


  • Organizational Affiliation

    Department of Biology, Molecular Basis of Disease Program, Georgia State University, Atlanta, GA 30303, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HIV-1 Protease
A, B
99Human immunodeficiency virus type 1 (BH5 ISOLATE)Mutation(s): 1 
Gene Names: gag-pol
EC: 3.4.23.16
UniProt
Find proteins for P04587 (Human immunodeficiency virus type 1 group M subtype B (isolate BH5))
Explore P04587 
Go to UniProtKB:  P04587
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04587
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ROC
Query on ROC

Download Ideal Coordinates CCD File 
E [auth A](2S)-N-[(2S,3R)-4-[(2S,3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1 -phenyl-butan-2-yl]-2-(quinolin-2-ylcarbonylamino)butanediamide
C38 H50 N6 O5
QWAXKHKRTORLEM-UGJKXSETSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
D [auth A],
F [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
NA
Query on NA

Download Ideal Coordinates CCD File 
C [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
ROC BindingDB:  3D1Y Ki: min: 0.04, max: 138 (nM) from 28 assay(s)
Kd: min: 0.31, max: 67 (nM) from 6 assay(s)
IC50: min: 0.2, max: 270 (nM) from 16 assay(s)
-TΔS: min: -8.03e+1, max: -2.80e+1 (kJ/mol) from 44 assay(s)
ΔH: min: -3.18e+1, max: 43.47 (kJ/mol) from 45 assay(s)
ΔG: min: -6.23e+1, max: -3.55e+1 (kJ/mol) from 44 assay(s)
Binding MOAD:  3D1Y Ki: 6 (nM) from 1 assay(s)
PDBBind:  3D1Y Ki: 6 (nM) from 1 assay(s)
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.05 Å
  • R-Value Free: 0.174 
  • R-Value Work: 0.150 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.72α = 90
b = 85.94β = 90
c = 46.38γ = 90
Software Package:
Software NamePurpose
SHELXmodel building
SHELXL-97refinement
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
SHELXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-05-27
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
  • Version 1.2: 2013-02-27
    Changes: Other
  • Version 1.3: 2021-10-20
    Changes: Database references, Derived calculations, Structure summary
  • Version 1.4: 2024-02-21
    Changes: Data collection