4IJ1

Bianthranilate-like analogue bound to anthranilate phosphoribosyltransferase (AnPRT; trpD) in absence of substrates.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.79 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.203 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Repurposing the Chemical Scaffold of the Anti-Arthritic Drug Lobenzarit to Target Tryptophan Biosynthesis in Mycobacterium tuberculosis.

Evans, G.L.Gamage, S.A.Bulloch, E.M.Baker, E.N.Denny, W.A.Lott, J.S.

(2014) Chembiochem 15: 852-864

  • DOI: https://doi.org/10.1002/cbic.201300628
  • Primary Citation of Related Structures:  
    4GIU, 4GKM, 4IJ1, 4M0R

  • PubMed Abstract: 

    The emergence of extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb) highlights the need for new therapeutics to treat tuberculosis. We are attempting to fast-track a targeted approach to drug design by generating analogues of a validated hit from molecular library screening that shares its chemical scaffold with a current therapeutic, the anti-arthritic drug Lobenzarit (LBZ). Our target, anthranilate phosphoribosyltransferase (AnPRT), is an enzyme from the tryptophan biosynthetic pathway in Mtb. A bifurcated hydrogen bond was found to be a key feature of the LBZ-like chemical scaffold and critical for enzyme inhibition. We have determined crystal structures of compounds in complex with the enzyme that indicate that the bifurcated hydrogen bond assists in orientating compounds in the correct conformation to interact with key residues in the substrate-binding tunnel of Mtb-AnPRT. Characterising the inhibitory potency of the hit and its analogues in different ways proved useful, due to the multiple substrates and substrate binding sites of this enzyme. Binding in a site other than the catalytic site was found to be associated with partial inhibition. An analogue, 2-(2-5-methylcarboxyphenylamino)-3-methylbenzoic acid, that bound at the catalytic site and caused complete, rather than partial, inhibition of enzyme activity was found. Therefore, we designed and synthesised an extended version of the scaffold on the basis of this observation. The resultant compound, 2,6-bis-(2-carboxyphenylamino)benzoate, is a 40-fold more potent inhibitor of the enzyme than the original hit and provides direction for further structure-based drug design.


  • Organizational Affiliation

    School of Biological Sciences, Faculty of Science, University of Auckland, Private Bag 92019, Auckland, 1142 (New Zealand). g.evans@auckland.ac.nz.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Anthranilate phosphoribosyltransferase
A, B
380Mycobacterium tuberculosisMutation(s): 0 
Gene Names: MT2248MTCY190.03cRv2192ctrpD
EC: 2.4.2.18
UniProt
Find proteins for P9WFX5 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WFX5 
Go to UniProtKB:  P9WFX5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WFX5
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
17C
Query on 17C

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B]
2,2'-iminodibenzoic acid
C14 H11 N O4
ZFRNOTZQUGWMQN-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B],
I [auth B],
J [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
IMD
Query on IMD

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A]
IMIDAZOLE
C3 H5 N2
RAXXELZNTBOGNW-UHFFFAOYSA-O
Binding Affinity Annotations 
IDSourceBinding Affinity
17C Binding MOAD:  4IJ1 Ki: 4000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.79 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.203 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 94.799α = 90
b = 78.05β = 111
c = 101.973γ = 90
Software Package:
Software NamePurpose
Blu-Icedata collection
PHASERphasing
PHENIXrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-12-25
    Type: Initial release
  • Version 1.1: 2014-05-21
    Changes: Database references
  • Version 1.2: 2017-11-15
    Changes: Refinement description
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description