4HVC

Crystal structure of human prolyl-tRNA synthetase in complex with halofuginone and ATP analogue

4HVC の概要

• エントリーDOI: 10.2210/pdb4hvc/pdb
• 分子名称: Bifunctional glutamate/proline--tRNA ligase, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, 7-bromo-6-chloro-3-{3-[(2R,3S)-3-hydroxypiperidin-2-yl]-2-oxopropyl}quinazolin-4(3H)-one, ... (6 entities in total)
• 機能のキーワード: ligase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytosol : P07814
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 120148.09

構造登録者

Zhou, H.,Sun, L.,Yang, X.L.,Schimmel, P. (登録日: 2012-11-06, 公開日: 2013-01-02, 最終更新日: 2024-02-28)

主引用文献

Zhou, H.,Sun, L.,Yang, X.L.,Schimmel, P.
ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase.
Nature, 494:121-124, 2012

PubMed Abstract: Febrifugine is the active component of the Chinese herb Chang Shan (Dichroa febrifuga Lour.), which has been used for treating malaria-induced fever for about 2,000 years. Halofuginone (HF), the halogenated derivative of febrifugine, has been tested in clinical trials for potential therapeutic applications in cancer and fibrotic disease. Recently, HF was reported to inhibit T(H)17 cell differentiation by activating the amino acid response pathway, through inhibiting human prolyl-transfer RNA synthetase (ProRS) to cause intracellular accumulation of uncharged tRNA. Curiously, inhibition requires the presence of unhydrolysed ATP. Here we report an unusual 2.0 Å structure showing that ATP directly locks onto and orients two parts of HF onto human ProRS, so that one part of HF mimics bound proline and the other mimics the 3' end of bound tRNA. Thus, HF is a new type of ATP-dependent inhibitor that simultaneously occupies two different substrate binding sites on ProRS. Moreover, our structure indicates a possible similar mechanism of action for febrifugine in malaria treatment. Finally, the elucidation here of a two-site modular targeting activity of HF raises the possibility that substrate-directed capture of similar inhibitors might be a general mechanism that could be applied to other synthetases.

PubMed: 23263184
DOI: 10.1038/nature11774

実験手法

X-RAY DIFFRACTION (2 Å)