5XIJ

Crystal Structure of Toxoplasma gondii Prolyl-tRNA Synthetase (TgPRS) in complex with Inhibitor 9

5XIJ の概要

• エントリーDOI: 10.2210/pdb5xij/pdb
• 関連するPDBエントリー: 5XIF 5XIG 5XIH 5XII 5XIK 5XIL 5XIO 5XIP 5XIQ
• 分子名称: Prolyl-tRNA synthetase (ProRS), PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: protein translation, prs, synthetase, inhibitor, infectious disease, ligase
• 由来する生物種: Toxoplasma gondii (strain ATCC 50611 / Me49)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 235181.68

構造登録者

Jain, V.,Manickam, Y.,Sharma, A. (登録日: 2017-04-26, 公開日: 2018-03-07, 最終更新日: 2023-11-22)

主引用文献

Jain, V.,Yogavel, M.,Kikuchi, H.,Oshima, Y.,Hariguchi, N.,Matsumoto, M.,Goel, P.,Touquet, B.,Jumani, R.S.,Tacchini-Cottier, F.,Harlos, K.,Huston, C.D.,Hakimi, M.A.,Sharma, A.
Targeting Prolyl-tRNA Synthetase to Accelerate Drug Discovery against Malaria, Leishmaniasis, Toxoplasmosis, Cryptosporidiosis, and Coccidiosis
Structure, 25:1495-1505.e6, 2017

PubMed Abstract: Developing anti-parasitic lead compounds that act on key vulnerabilities are necessary for new anti-infectives. Malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis and coccidiosis together kill >500,000 humans annually. Their causative parasites Plasmodium, Leishmania, Toxoplasma, Cryptosporidium and Eimeria display high conservation in many housekeeping genes, suggesting that these parasites can be attacked by targeting invariant essential proteins. Here, we describe selective and potent inhibition of prolyl-tRNA synthetases (PRSs) from the above parasites using a series of quinazolinone-scaffold compounds. Our PRS-drug co-crystal structures reveal remarkable active site plasticity that accommodates diversely substituted compounds, an enzymatic feature that can be leveraged for refining drug-like properties of quinazolinones on a per parasite basis. A compound we termed In-5 exhibited a unique double conformation, enhanced drug-like properties, and cleared malaria in mice. It thus represents a new lead for optimization. Collectively, our data offer insights into the structure-guided optimization of quinazolinone-based compounds for drug development against multiple human eukaryotic pathogens.

PubMed: 28867614
DOI: 10.1016/j.str.2017.07.015

実験手法

X-RAY DIFFRACTION (2.5 Å)