7F9C

Homo sapiens Prolyl-tRNA Synthetase (HsPRS) in Complex with L-proline and compound L96

7F9C の概要

• エントリーDOI: 10.2210/pdb7f9c/pdb
• 分子名称: Bifunctional glutamate/proline--tRNA ligase, 4-[(3S)-3-cyano-3-cyclopropyl-2-oxidanylidene-pyrrolidin-1-yl]-N-[[3-fluoranyl-5-(5-methoxypyridin-3-yl)phenyl]methyl]-6-methyl-pyridine-2-carboxamide, ZINC ION, ... (7 entities in total)
• 機能のキーワード: protein translation, inhibitor, prs, atp pocket, ligase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 116804.11

構造登録者

Malhotra, N.,Manickam, Y.,Sharma, A. (登録日: 2021-07-04, 公開日: 2022-07-06, 最終更新日: 2023-11-29)

主引用文献

Yogavel, M.,Bougdour, A.,Mishra, S.,Malhotra, N.,Chhibber-Goel, J.,Bellini, V.,Harlos, K.,Laleu, B.,Hakimi, M.A.,Sharma, A.
Targeting prolyl-tRNA synthetase via a series of ATP-mimetics to accelerate drug discovery against toxoplasmosis.
Plos Pathog., 19:e1011124-e1011124, 2023

PubMed Abstract: The prolyl-tRNA synthetase (PRS) is a validated drug target for febrifugine and its synthetic analog halofuginone (HFG) against multiple apicomplexan parasites including Plasmodium falciparum and Toxoplasma gondii. Here, a novel ATP-mimetic centered on 1-(pyridin-4-yl) pyrrolidin-2-one (PPL) scaffold has been validated to bind to Toxoplasma gondii PRS and kill toxoplasma parasites. PPL series exhibited potent inhibition at the cellular (T. gondii parasites) and enzymatic (TgPRS) levels compared to the human counterparts. Cell-based chemical mutagenesis was employed to determine the mechanism of action via a forward genetic screen. Tg-resistant parasites were analyzed with wild-type strain by RNA-seq to identify mutations in the coding sequence conferring drug resistance by computational analysis of variants. DNA sequencing established two mutations, T477A and T592S, proximal to terminals of the PPL scaffold and not directly in the ATP, tRNA, or L-pro sites, as supported by the structural data from high-resolution crystal structures of drug-bound enzyme complexes. These data provide an avenue for structure-based activity enhancement of this chemical series as anti-infectives.

PubMed: 36854028
DOI: 10.1371/journal.ppat.1011124

実験手法

X-RAY DIFFRACTION (2.196 Å)