Discovery of a novel prolyl-tRNA synthetase inhibitor and elucidation of its binding mode to the ATP site in complex with l-proline

Biochemical and Biophysical Research Communications
Ryutaro AdachiTomohiro Kawamoto

Abstract

Prolyl-tRNA synthetase (PRS) is a member of the aminoacyl-tRNA synthetase family of enzymes and catalyzes the synthesis of prolyl-tRNAPro using ATP, l-proline, and tRNAPro as substrates. An ATP-dependent PRS inhibitor, halofuginone, was shown to suppress autoimmune responses, suggesting that the inhibition of PRS is a potential therapeutic approach for inflammatory diseases. Although a few PRS inhibitors have been derivatized from natural sources or substrate mimetics, small-molecule human PRS inhibitors have not been reported. In this study, we discovered a novel series of pyrazinamide PRS inhibitors from a compound library using pre-transfer editing activity of human PRS enzyme. Steady-state biochemical analysis on the inhibitory mode revealed its distinctive characteristics of inhibition with proline uncompetition and ATP competition. The binding activity of a representative compound was time-dependently potentiated by the presence of l-proline with Kd of 0.76 nM. Thermal shift assays demonstrated the stabilization of PRS in complex with l-proline and pyrazinamide PRS inhibitors. The binding mode of the PRS inhibitor to the ATP site of PRS enzyme was elucidated using the ternary complex crystal structure with l-proline. The ...Continue Reading

Citations

May 22, 2019·The Journal of Biological Chemistry·Michelle YamJianhai Du
Nov 30, 2019·Cell Death & Disease·Anzheng NieDongsheng Yu
Oct 18, 2020·Chemical Biology & Drug Design·Daria NawrotJan Zitko
Feb 14, 2021·International Journal of Molecular Sciences·Luping PangArthur Van Aerschot
May 17, 2021·Chemical Biology & Drug Design·Umar NdagiNdumiso N Mhlongo
Apr 11, 2020·Journal of Medicinal Chemistry·Martin Juhás, Jan Zitko

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