3QAA

HIV-1 wild type protease with a substituted bis-Tetrahydrofuran inhibitor, GRL-044-10A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.172 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Design of substituted bis-Tetrahydrofuran (bis-THF)-derived Potent HIV-1 Protease Inhibitors, Protein-ligand X-ray Structure, and Convenient Syntheses of bis-THF and Substituted bis-THF Ligands.

Ghosh, A.K.Martyr, C.D.Steffey, M.Wang, Y.F.Agniswamy, J.Amano, M.Weber, I.T.Mitsuya, H.

(2011) ACS Med Chem Lett 2: 298-302

  • DOI: https://doi.org/10.1021/ml100289m
  • Primary Citation of Related Structures:  
    3QAA

  • PubMed Abstract: 

    We investigated substituted bis-THF-derived HIV-1 protease inhibitors in order to enhance ligand-binding site interactions in the HIV-1 protease active site. In this context, we have carried out convenient syntheses of optically active bis-THF and C4-substituted bis-THF ligands using a [2,3]-sigmatropic rearrangement as the key step. The synthesis provided convenient access to a number of substituted bis-THF derivatives. Incorporation of these ligands led to a series of potent HIV-1 protease inhibitors. Inhibitor 23c turned out to be the most potent (K(i) = 2.9 pM; IC(50) = 2.4 nM) among the inhibitors. An X-ray structure of 23c-bound HIV-1 protease showed extensive interactions of the inhibitor with the protease active site, including a unique water-mediated hydrogen bond to the Gly-48 amide NH in the S2 site.


  • Organizational Affiliation

    Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HIV-1 Protease
A, B
99Human immunodeficiency virus 1Mutation(s): 5 
Gene Names: pol
EC: 3.4.23.16
UniProt
Find proteins for P03366 (Human immunodeficiency virus type 1 group M subtype B (isolate BH10))
Explore P03366 
Go to UniProtKB:  P03366
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03366
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
G04
Query on G04

Download Ideal Coordinates CCD File 
C [auth A](3R,3aS,4R,6aR)-4-methoxyhexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-3-hydroxy-4-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}-1-phenylbutan-2-yl]carbamate
C29 H40 N2 O9 S
YOBNNQXGIZIFRK-ZXOGEQNHSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
G [auth B],
H [auth B],
I [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
CL
Query on CL

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

Download Ideal Coordinates CCD File 
D [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
G04 PDBBind:  3QAA Ki: 2.90e-3 (nM) from 1 assay(s)
BindingDB:  3QAA Ki: min: 2.90e-3, max: 0.04 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.172 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.435α = 90
b = 86.112β = 90
c = 46.032γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHASESphasing
SHELXL-97refinement
HKL-2000data reduction
HKL-2000data 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: 2011-12-21
    Type: Initial release
  • Version 1.1: 2018-04-18
    Changes: Data collection, Database references
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description