4JIT

Crystal Structure of E. coli XGPRT in complex with (S)-3-(Guanin-9-yl)pyrrolidin-N-ylacetylphosphonic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.213 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Inhibition of the Escherichia coli 6-oxopurine phosphoribosyltransferases by nucleoside phosphonates: potential for new antibacterial agents.

Keough, D.T.Hockova, D.Rejman, D.Spacek, P.Vrbkova, S.Krecmerova, M.Eng, W.S.Jans, H.West, N.P.Naesens, L.M.de Jersey, J.Guddat, L.W.

(2013) J Med Chem 56: 6967-6984

  • DOI: https://doi.org/10.1021/jm400779n
  • Primary Citation of Related Structures:  
    4JIT, 4JLS

  • PubMed Abstract: 

    Escherichia coli (Ec) cells possess two purine salvage enzymes: xanthine-guanine phosphoribosyltransferase (XGPRT) and hypoxanthine phosphoribosyltransferase (HPRT). EcXGPRT shares a common structural feature with other members of this family, a flexible loop that closes over the active site during catalysis. The replacement of six of these amino acids by alanine has no effect on the Km for the two substrates. However, the Ki for the nucleoside monophosphate increases by 27-fold, and the kcat is reduced by ∼200-fold. Nucleoside phosphonates (NP) are good inhibitors of EcXGPRT and EcHPRT, with Ki values as low as 10 nM. In the absence of the flexible loop, these values increase by 5- to 30-fold, indicating the importance of the loop for high-affinity inhibition. Crystal structures of two NPs in complex with EcXGPRT explain the tight binding. Prodrugs of NPs with low Ki values for EcXGPRT or EcHPRT exhibit IC50 values between 5 and 23 μM against Mycobacterium tuberculosis in cell-based assays, suggesting that these compounds are therapeutic leads against pathogenic bacteria.


  • Organizational Affiliation

    The School of Chemistry and Molecular Biosciences, The University of Queensland , Brisbane, 4072 QLD, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Xanthine phosphoribosyltransferase
A, B, C, D
152Escherichia coli str. K-12 substr. MDS42Mutation(s): 0 
Gene Names: gptECMDS42_0227
EC: 2.4.2.22
UniProt
Find proteins for P0A9M5 (Escherichia coli (strain K12))
Explore P0A9M5 
Go to UniProtKB:  P0A9M5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0A9M5
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3ZF
Query on 3ZF

Download Ideal Coordinates CCD File 
E [auth B],
F [auth C]
{2-[(3S)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)pyrrolidin-1-yl]-2-oxoethyl}phosphonic acid
C11 H15 N6 O5 P
DPSMTUGMQGDYNX-LURJTMIESA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.213 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 94.066α = 90
b = 94.066β = 90
c = 162.633γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
PHASERphasing
PHENIXrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2014-12-24
    Type: Initial release
  • Version 1.1: 2024-02-28
    Changes: Data collection, Database references, Derived calculations