4YDQ

Crystal Structure of Prolyl-tRNA Synthetase (PRS) from Plasmodium falciparum in complex with Halofuginone and AMPPNP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.186 

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This is version 1.1 of the entry. See complete history


Literature

Structure of Prolyl-tRNA Synthetase-Halofuginone Complex Provides Basis for Development of Drugs against Malaria and Toxoplasmosis

Jain, V.Yogavel, M.Oshima, Y.Kikuchi, H.Touquet, B.Hakimi, M.A.Sharma, A.

(2015) Structure 23: 819-829

  • DOI: https://doi.org/10.1016/j.str.2015.02.011
  • Primary Citation of Related Structures:  
    4YDQ

  • PubMed Abstract: 

    The Chinese herb Dichroa febrifuga has traditionally treated malaria-associated fever. Its active component febrifugine (FF) and derivatives such as halofuginone (HF) are potent anti-malarials. Here, we show that FF-based derivatives arrest parasite growth by direct interaction with and inhibition of the protein translation enzyme prolyl-tRNA synthetase (PRS). Dual administration of inhibitors that target different tRNA synthetases suggests high utility of these drug targets. We reveal the ternary complex structure of PRS-HF and adenosine 5'-(β,γ-imido)triphosphate where the latter facilitates HF integration into the PRS active site. Structural analyses also highlight spaces within the PRS architecture for HF derivatization of its quinazolinone, but not piperidine, moiety. We also show a remarkable ability of HF to kill the related human parasite Toxoplasma gondii, suggesting wider HF efficacy against parasitic PRSs. Hence, our cell-, enzyme-, and structure-based data on FF-based inhibitors strengthen the case for their inclusion in anti-malarial and anti-toxoplasmosis drug development efforts.


  • Organizational Affiliation

    Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi 110067, India.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proline--tRNA ligase
A, B
497Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: proRSPFL0670c
EC: 6.1.1.15
UniProt
Find proteins for Q8I5R7 (Plasmodium falciparum (isolate 3D7))
Explore Q8I5R7 
Go to UniProtKB:  Q8I5R7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8I5R7
Sequence Annotations
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  • Reference Sequence
Small Molecules
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.186 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 81.026α = 90
b = 88.929β = 96.71
c = 86.295γ = 90
Software Package:
Software NamePurpose
HKL-2000data scaling
HKL-2000data reduction
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-05-20
    Type: Initial release
  • Version 1.1: 2023-11-08
    Changes: Advisory, Data collection, Database references, Derived calculations, Refinement description, Source and taxonomy, Structure summary