3QR9

Anthranilate phosphoribosyltransferase (trpD) from Mycobacterium tuberculosis (apo structure)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.87 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.188 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

The Substrate Capture Mechanism of Mycobacterium tuberculosis Anthranilate Phosphoribosyltransferase Provides a Mode for Inhibition.

Castell, A.Short, F.L.Evans, G.L.Cookson, T.V.Bulloch, E.M.Joseph, D.D.Lee, C.E.Parker, E.J.Baker, E.N.Lott, J.S.

(2013) Biochemistry 52: 1776-1787

  • DOI: https://doi.org/10.1021/bi301387m
  • Primary Citation of Related Structures:  
    3QQS, 3QR9, 3QS8, 3R6C, 3R88, 3TWP, 3UU1

  • PubMed Abstract: 

    Anthranilate phosphoribosyltransferase (AnPRT, EC 2.4.2.18) is a homodimeric enzyme that catalyzes the reaction between 5'-phosphoribosyl 1'-pyrophosphate (PRPP) and anthranilate, as part of the tryptophan biosynthesis pathway. Here we present the results of the first chemical screen for inhibitors against Mycobacterium tuberculosis AnPRT (Mtb-AnPRT), along with crystal structures of Mtb-AnPRT in complex with PRPP and several inhibitors. Previous work revealed that PRPP is bound at the base of a deep cleft in Mtb-AnPRT and predicted two anthranilate binding sites along the tunnel leading to the PRPP binding site. Unexpectedly, the inhibitors presented here almost exclusively bound at the entrance of the tunnel, in the presumed noncatalytic anthranilate binding site, previously hypothesized to have a role in substrate capture. The potencies of the inhibitors were measured, yielding Ki values of 1.5-119 μM, with the strongest inhibition displayed by a bianthranilate compound that makes hydrogen bond and salt bridge contacts with Mtb-AnPRT via its carboxyl groups. Our results reveal how the substrate capture mechanism of AnPRT can be exploited to inhibit the enzyme's activity and provide a scaffold for the design of improved Mtb-AnPRT inhibitors that may ultimately form the basis of new antituberculosis drugs with a novel mode of action.


  • Organizational Affiliation

    Maurice Wilkins Centre for Molecular Biodiscovery and School of Biological Sciences, University of Auckland , 3 Symonds Street, Auckland 1142, New Zealand.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Anthranilate phosphoribosyltransferase
A, B
377Mycobacterium tuberculosisMutation(s): 0 
Gene Names: MT2248MTCY190.03ctrpD
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
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.87 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.188 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 79.465α = 90
b = 91.771β = 90
c = 120.085γ = 90
Software Package:
Software NamePurpose
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACTdata extraction
MAR345dtbdata collection

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-06-15
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2013-02-20
    Changes: Database references
  • Version 1.3: 2013-04-10
    Changes: Database references
  • Version 1.4: 2013-11-27
    Changes: Database references
  • Version 1.5: 2024-02-21
    Changes: Data collection, Database references, Derived calculations