7Y1H

Controlling fibrosis using compound with novel binding mode to prolyl-tRNA synthetase 1

7Y1H の概要

• エントリーDOI: 10.2210/pdb7y1h/pdb
• 分子名称: Bifunctional glutamate/proline--tRNA ligase, 1-(5-chloranyl-4-methyl-benzimidazol-1-yl)-3-[(2R,3S)-3-oxidanylpiperidin-2-yl]propan-2-one, ADENOSINE-5'-TRIPHOSPHATE, ... (6 entities in total)
• 機能のキーワード: prolyl-trna synthetase, inhibitor, fibrosis, binding mode, translation, translation-inhibitor complex, translation/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: 118060.75

構造登録者

Kim, S.,Yoon, I.,Son, J.,Park, S.,Hwang, K.Y. (登録日: 2022-06-08, 公開日: 2023-07-05, 最終更新日: 2023-11-29)

主引用文献

Yoon, I.,Kim, S.,Cho, M.,You, K.A.,Son, J.,Lee, C.,Suh, J.H.,Bae, D.J.,Kim, J.M.,Oh, S.,Park, S.,Kim, S.,Cho, S.H.,Park, S.,Bang, K.,Seo, M.,Kim, J.H.,Lee, B.,Park, J.S.,Hwang, K.Y.,Kim, S.
Control of fibrosis with enhanced safety via asymmetric inhibition of prolyl-tRNA synthetase 1.
Embo Mol Med, 15:e16940-e16940, 2023

PubMed Abstract: Prolyl-tRNA synthetase 1 (PARS1) has attracted much interest in controlling pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases. However, there are concerns about its catalytic inhibition for potential adverse effects on global protein synthesis. We developed a novel compound, DWN12088, whose safety was validated by clinical phase 1 studies, and therapeutic efficacy was shown in idiopathic pulmonary fibrosis model. Structural and kinetic analyses revealed that DWN12088 binds to catalytic site of each protomer of PARS1 dimer in an asymmetric mode with different affinity, resulting in decreased responsiveness at higher doses, thereby expanding safety window. The mutations disrupting PARS1 homodimerization restored the sensitivity to DWN12088, validating negative communication between PARS1 promoters for the DWN12088 binding. Thus, this work suggests that DWN12088, an asymmetric catalytic inhibitor of PARS1 as a novel therapeutic agent against fibrosis with enhanced safety.

PubMed: 37212275
DOI: 10.15252/emmm.202216940

実験手法

X-RAY DIFFRACTION (1.99 Å)