RCSB PDB - 4HEG: Crystal Structure of HIV-1 protease mutants R8Q complexed with inhibitor GRL-0519

 4HEG

Crystal Structure of HIV-1 protease mutants R8Q complexed with inhibitor GRL-0519


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.46 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.158 

Starting Model: experimental
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Ligand Structure Quality Assessment 

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Literature

Novel P2 tris-tetrahydrofuran group in antiviral compound 1 (GRL-0519) fills the S2 binding pocket of selected mutants of HIV-1 protease.

Zhang, H.Wang, Y.F.Shen, C.H.Agniswamy, J.Rao, K.V.Xu, C.X.Ghosh, A.K.Harrison, R.W.Weber, I.T.

(2013) J Med Chem 56: 1074-1083

  • DOI: https://doi.org/10.1021/jm301519z
  • Primary Citation of Related Structures:  
    4HDB, 4HDF, 4HDP, 4HE9, 4HEG

  • PubMed Abstract: 

    GRL-0519 (1) is a potent antiviral inhibitor of HIV-1 protease (PR) possessing tris-tetrahydrofuran (tris-THF) at P2. The high resolution X-ray crystal structures of inhibitor 1 in complexes with single substitution mutants PR(R8Q), PR(D30N), PR(I50V), PR(I54M), and PR(V82A) were analyzed in relation to kinetic data. The smaller valine side chain in PR(I50V) eliminated hydrophobic interactions with inhibitor and the other subunit consistent with 60-fold worse inhibition. Asn30 in PR(D30N) showed altered interactions with neighboring residues and 18-fold worse inhibition. Mutations V82A and I54M showed compensating structural changes consistent with 6-7-fold lower inhibition. Gln8 in PR(R8Q) replaced the ionic interactions of wild type Arg8 with hydrogen bond interactions without changing the inhibition significantly. The carbonyl oxygen of Gly48 showed two alternative conformations in all structures likely due to the snug fit of the large tris-THF group in the S2 subsite in agreement with high antiviral efficacy of 1 on resistant virus.


  • Organizational Affiliation

    Department of Biology, Georgia State University, Atlanta, Georgia 30303, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HIV-1 proteaseA [auth B],
B [auth A]
99Human immunodeficiency virus type 1 (BRU ISOLATE)Mutation(s): 6 
Gene Names: gag-pol
EC: 3.4.23.16
UniProt
Find proteins for P03367 (Human immunodeficiency virus type 1 group M subtype B (isolate BRU/LAI))
Explore P03367 
Go to UniProtKB:  P03367
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03367
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
G52
Query on G52

Download Ideal Coordinates CCD File 
C [auth A](3R,3aS,3bR,6aS,7aS)-octahydrodifuro[2,3-b:3',2'-d]furan-3-yl [(1S,2R)-1-benzyl-2-hydroxy-3-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}propyl]carbamate
C30 H40 N2 O9 S
QWMNYFXRFHGYGS-DDGGWZRMSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
G52 PDBBind:  4HEG Ki: 1.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.46 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.158 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.372α = 90
b = 85.957β = 90
c = 46.18γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHASERphasing
SHELXL-97refinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted G52Click on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-08-21
    Type: Initial release
  • Version 1.1: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description