4KB9

Crystal structure of wild-type HIV-1 protease with novel tricyclic P2-ligands GRL-0739A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.29 Å
  • R-Value Free: 0.180 
  • R-Value Work: 0.139 
  • R-Value Observed: 0.139 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Highly Potent HIV-1 Protease Inhibitors with Novel Tricyclic P2 Ligands: Design, Synthesis, and Protein-Ligand X-ray Studies.

Ghosh, A.K.Parham, G.L.Martyr, C.D.Nyalapatla, P.R.Osswald, H.L.Agniswamy, J.Wang, Y.F.Amano, M.Weber, I.T.Mitsuya, H.

(2013) J Med Chem 56: 6792-6802

  • DOI: https://doi.org/10.1021/jm400768f
  • Primary Citation of Related Structures:  
    4KB9

  • PubMed Abstract: 

    The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor's potent antiviral activity and excellent resistance profiles.


  • Organizational Affiliation

    Department of Chemistry and Department of Medicinal Chemistry, Purdue University , West Lafayette, Indiana 47907, United States.


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
EC: 3.4.23.16
UniProt
Find proteins for Q7SSI0 (Human immunodeficiency virus 1)
Explore Q7SSI0 
Go to UniProtKB:  Q7SSI0
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ7SSI0
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
G79
Query on G79

Download Ideal Coordinates CCD File 
C [auth A](3aR,3bR,4S,7aR,8aS)-decahydrofuro[2,3-b][1]benzofuran-4-yl [(2S,3R)-3-hydroxy-4-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}-1-phenylbutan-2-yl]carbamate
C32 H44 N2 O8 S
ORJPZJYXIFRPSW-OTTDUJIMSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
J [auth B],
K [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
I [auth B]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
CL
Query on CL

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

Download Ideal Coordinates CCD File 
G [auth B]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
G79 Binding MOAD:  4KB9 Ki: 1.00e-2 (nM) from 1 assay(s)
BindingDB:  4KB9 Ki: 1.00e-2 (nM) from 1 assay(s)
PDBBind:  4KB9 Ki: 1.00e-2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.29 Å
  • R-Value Free: 0.180 
  • R-Value Work: 0.139 
  • R-Value Observed: 0.139 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.477α = 90
b = 86.3β = 90
c = 46.045γ = 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: 2013-09-04
    Type: Initial release
  • Version 1.1: 2013-09-25
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description