4YDQ

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

4YDQ の概要

• エントリーDOI: 10.2210/pdb4ydq/pdb
• 関連するPDBエントリー: 4HVC 4TWA
• 分子名称: 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)
• 機能のキーワード: prolyl-trna synthetase, complex, halofuginone, malaria, ligase
• 由来する生物種: Plasmodium falciparum
• 細胞内の位置: Cytoplasm : Q8I5R7
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 117492.74

構造登録者

Jain, V.,Yogavel, M.,Sharma, A. (登録日: 2015-02-23, 公開日: 2015-05-20, 最終更新日: 2023-11-08)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.3 Å)