6U7P

HIV-1 wild type protease with GRL-03119A, with phenyl-boronic-acid as P2'-ligand and with a hexahydro-4H-furo-pyran as the P2-ligand


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.13 Å
  • R-Value Free: 0.141 
  • R-Value Work: 0.125 
  • R-Value Observed: 0.126 

wwPDB Validation   3D Report Full Report

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This is version 1.3 of the entry. See complete history


Literature

Potent HIV-1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein-Ligand X-ray Structural Studies.

Ghosh, A.K.Xia, Z.Kovela, S.Robinson, W.L.Johnson, M.E.Kneller, D.W.Wang, Y.F.Aoki, M.Takamatsu, Y.Weber, I.T.Mitsuya, H.

(2019) ChemMedChem 14: 1863-1872

  • DOI: https://doi.org/10.1002/cmdc.201900508
  • Primary Citation of Related Structures:  
    6U7O, 6U7P

  • PubMed Abstract: 

    We report the synthesis and biological evaluation of phenylcarboxylic acid and phenylboronic acid containing HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. Inhibitors bearing bis-THF ligand as P2 ligand and phenylcarboxylic acids and carboxamide as the P2' ligands, showed very potent HIV-1 protease inhibitory activity. However, carboxylic acid containing inhibitors showed very poor antiviral activity relative to carboxamide-derived inhibitors which showed good antiviral IC 50 value. Boronic acid derived inhibitor with bis-THF as the P2 ligand showed very potent enzyme inhibitory activity, but it showed lower antiviral activity than darunavir in the same assay. Boronic acid containing inhibitor with a P2-Crn-THF ligand also showed potent enzyme K i but significantly decreased antiviral activity. We have evaluated antiviral activity against a panel of highly drug-resistant HIV-1 variants. One of the inhibitors maintained good antiviral activity against HIV DRV R P20 and HIV DRV R P30 viruses. We have determined high resolution X-ray structures of two synthetic inhibitors bound to HIV-1 protease and obtained molecular insight into the ligand-binding site interactions.


  • Organizational Affiliation

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


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
UniProt
Find proteins for Q5RZ08 (Human immunodeficiency virus 1)
Explore Q5RZ08 
Go to UniProtKB:  Q5RZ08
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ5RZ08
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
B4R (Subject of Investigation/LOI)
Query on B4R

Download Ideal Coordinates CCD File 
C [auth A]{4-[{(2R,3S)-3-[({[(3aS,4S,7aR)-hexahydro-4H-furo[2,3-b]pyran-4-yl]oxy}carbonyl)amino]-2-hydroxy-4-phenylbutyl}(2-methylpropyl)sulfamoyl]phenyl}boronic acid
C28 H39 B N2 O9 S
LVYBBLQFCOXKLU-UIPNDDLNSA-N
GOL
Query on GOL

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

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J [auth B]FORMIC ACID
C H2 O2
BDAGIHXWWSANSR-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
G [auth B],
H [auth B],
I [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
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.13 Å
  • R-Value Free: 0.141 
  • R-Value Work: 0.125 
  • R-Value Observed: 0.126 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.491α = 90
b = 86.097β = 90
c = 46.086γ = 90
Software Package:
Software NamePurpose
HKL-2000data scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)United StatesAI150466
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesAI150461

Revision History  (Full details and data files)

  • Version 1.0: 2019-10-09
    Type: Initial release
  • Version 1.1: 2019-11-20
    Changes: Database references
  • Version 1.2: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.3: 2023-10-11
    Changes: Data collection, Database references, Derived calculations, Refinement description