4YDQ

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

Summary for 4YDQ

• Entry DOI: 10.2210/pdb4ydq/pdb
• Related: 4HVC 4TWA
• Descriptor: Proline--tRNA ligase, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, 7-bromo-6-chloro-3-{3-[(2R,3S)-3-hydroxypiperidin-2-yl]-2-oxopropyl}quinazolin-4(3H)-one, ... (5 entities in total)
• Functional Keywords: prolyl-trna synthetase, complex, halofuginone, malaria, ligase
• Biological source: Plasmodium falciparum
• Cellular location: Cytoplasm : Q8I5R7
• Total number of polymer chains: 2
• Total formula weight: 117492.74

Authors

Jain, V.,Yogavel, M.,Sharma, A. (deposition date: 2015-02-23, release date: 2015-05-20, Last modification date: 2023-11-08)

Primary citation

Jain, V.,Yogavel, M.,Oshima, Y.,Kikuchi, H.,Touquet, B.,Hakimi, M.A.,Sharma, A.
Structure of Prolyl-tRNA Synthetase-Halofuginone Complex Provides Basis for Development of Drugs against Malaria and Toxoplasmosis
Structure, 23:819-829, 2015

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.

PubMed: 25817387
DOI: 10.1016/j.str.2015.02.011

Experimental method

X-RAY DIFFRACTION (2.3 Å)