ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase

• Published in: Nature (London) 2013-02, Vol.494 (7435), p.121-124
• Main Authors: Zhou, Huihao, Sun, Litao, Yang, Xiang-Lei, Schimmel, Paul
• Format: Article
• Language: English
• Subjects: 631/45/612; 631/535/1266; 631/92/609; 692/308/153; 692/699/255/1629; 692/700/565; Adenosine triphosphate; Adenosine Triphosphate - chemistry; Adenosine Triphosphate - metabolism; Adenosine Triphosphate - pharmacology; Amino acids; Amino Acyl-tRNA Synthetases - antagonists & inhibitors; Amino Acyl-tRNA Synthetases - chemistry; Amino Acyl-tRNA Synthetases - metabolism; Antimalarials - chemistry; Antimalarials - pharmacology; ATP; Binding Sites; Cell differentiation; Crystallography, X-Ray; Enzymes; Health aspects; Herbal Medicine; Humanities and Social Sciences; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; letter; Ligands; Malaria; Medicine, Chinese Traditional; Models, Molecular; multidisciplinary; Physiological aspects; Piperidines - chemistry; Piperidines - metabolism; Piperidines - pharmacology; Proline - chemistry; Proline - metabolism; Protein biosynthesis; Protein synthesis; Proteins; Quinazolines - chemistry; Quinazolines - pharmacology; Quinazolinones - chemistry; Quinazolinones - metabolism; Quinazolinones - pharmacology; RNA, Transfer - chemistry; RNA, Transfer - metabolism; Science; Transfer RNA; Vector-borne diseases
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11774

The crystal structure of prolyl tRNA synthetase simultaneously bound to its substrate ATP and its inhibitor halofuginone, a derivative of a compound used to treat malaria, indicates that (through interactions with ATP) halofuginone occupies both the amino acid and tRNA binding sites on the synthetase, revealing a new model for developing synthetase inhibitors. Mechanism of action of a herbal antimalarial The halogenated derivative of an active ingredient in Chinese traditional medicine used as an antimalarial treatment, halofuginone (HF), is currently in clinical trials. HF is known to inhibit prolyl-tRNA synthetase (ProRS), resulting in an accumulation of uncharged tRNAs. Paul Schimmel and colleagues have solved the crystal structure of ProRS bound to ATP and HF. They find that ATP helps to lock the drug on ProRS so that it occupies two substrate binding sites — one for proline and the other for the 3′ end of the tRNA. The authors suggest that this information might be used to develop other synthetase inhibitors that would occupy both sites in a modular fashion. Febrifugine is the active component of the Chinese herb Chang Shan ( Dichroa febrifuga Lour.) 1 , 2 , 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 3 , 4 , 5 , 6 . Recently, HF was reported to inhibit T H 17 cell differentiation by activating the amino acid response pathway 7 , through inhibiting human prolyl-transfer RNA synthetase (ProRS) to cause intracellular accumulation of uncharged tRNA 8 , 9 . 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.