7OT0

Human Prolyl-tRNA Synthetase in Complex with L-proline and Compound 4h

7OT0 の概要

• エントリーDOI: 10.2210/pdb7ot0/pdb
• 関連するPDBエントリー: 7OT1 7OT2 7OT3
• 分子名称: Bifunctional glutamate/proline--tRNA ligase, PROLINE, 3-[(2-chlorophenyl)methylamino]pyrazine-2-carboxamide, ... (6 entities in total)
• 機能のキーワード: beta barrel, trna synthetase, protein-inhibitor complex, ligase
• 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: 117236.46

構造登録者

Pang, L.,Zitko, J.,Strelkov, S.V.,Weeks, S.D. (登録日: 2021-06-09, 公開日: 2021-07-28, 最終更新日: 2024-01-31)

主引用文献

Pang, L.,Weeks, S.D.,Juhas, M.,Strelkov, S.V.,Zitko, J.,Van Aerschot, A.
Towards Novel 3-Aminopyrazinamide-Based Prolyl-tRNA Synthetase Inhibitors: In Silico Modelling, Thermal Shift Assay and Structural Studies.
Int J Mol Sci, 22:-, 2021

PubMed Abstract: Human cytosolic prolyl-tRNA synthetase (HcProRS) catalyses the formation of the prolyl-tRNA, playing an important role in protein synthesis. Inhibition of HcProRS activity has been shown to have potential benefits in the treatment of fibrosis, autoimmune diseases and cancer. Recently, potent pyrazinamide-based inhibitors were identified by a high-throughput screening (HTS) method, but no further elaboration was reported. The pyrazinamide core is a bioactive fragment found in numerous clinically validated drugs and has been subjected to various modifications. Therefore, we applied a virtual screening protocol to our in-house library of pyrazinamide-containing small molecules, searching for potential novel HcProRS inhibitors. We identified a series of 3-benzylaminopyrazine-2-carboxamide derivatives as positive hits. Five of them were confirmed by a thermal shift assay (TSA) with the best compounds and showing EC values of 3.77 and 7.34 µM, respectively, in the presence of 1 mM of proline (Pro) and 3.45 µM enzyme concentration. Co-crystal structures of HcProRS in complex with these compounds and Pro confirmed the initial docking studies and show how the Pro facilitates binding of the ligands that compete with ATP substrate. Modelling into other human class II aminoacyl-tRNA synthetases (aaRSs) indicated that the subtle differences in the ATP binding site of these enzymes likely contribute to its potential selective binding of HcProRS. Taken together, this study successfully identified novel HcProRS binders from our anti-tuberculosis in-house compound library, displaying opportunities for repurposing old drug candidates for new applications such as therapeutics in HcProRS-related diseases.

PubMed: 34360555
DOI: 10.3390/ijms22157793

実験手法

X-RAY DIFFRACTION (2.32 Å)