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

Zhou H, Sun L, Yang XL, Schimmel P - Nature (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: The Skaggs Institute for Chemical Biology, Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

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.

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Related in: MedlinePlus

FF blocks ProRSFebrifugine (FF) docked to the active site of P. falcipaurm ProRS (UniProtKB code Q8I5R7). ProRS and FF are colored as cyan and yellow, respectively. The hydrogen bonds are indicated with dashes. The P. falciparum ProRS structure was generated by the protein structure homology-modeling sever SWISS-MODEL20. FF was docked into the P. falciparum ProRS active site based on the structure of ProRS:halofuginone:ATPa complex, while ATP was docked based on the structure of the T. thermophilus ProRS:tRNA:ATP complex (PDB code 1H4Q).
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Figure 4: FF blocks ProRSFebrifugine (FF) docked to the active site of P. falcipaurm ProRS (UniProtKB code Q8I5R7). ProRS and FF are colored as cyan and yellow, respectively. The hydrogen bonds are indicated with dashes. The P. falciparum ProRS structure was generated by the protein structure homology-modeling sever SWISS-MODEL20. FF was docked into the P. falciparum ProRS active site based on the structure of ProRS:halofuginone:ATPa complex, while ATP was docked based on the structure of the T. thermophilus ProRS:tRNA:ATP complex (PDB code 1H4Q).

Mentions: HF is a halogenated derivative of febrifugine, which is the bioactive constituent in the Chang Shan herb that has long been used to treat malaria. The human and malaria parasite P. falciparum ProRS binding sites are highly conversed (Supplementary Fig. 4). With that in mind, using our ATP-dependent docking of HF to human ProRS as a template, we were able to show the potential for docking of FF to P. falcipaurm ProRS (Fig. 4). Thus, our analysis suggests malarial ProRS may also be the target of FF. This possibility could also explain why the killing effect of FF on P. falciparum in culture is reversed by proline8.


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

Zhou H, Sun L, Yang XL, Schimmel P - Nature (2012)

FF blocks ProRSFebrifugine (FF) docked to the active site of P. falcipaurm ProRS (UniProtKB code Q8I5R7). ProRS and FF are colored as cyan and yellow, respectively. The hydrogen bonds are indicated with dashes. The P. falciparum ProRS structure was generated by the protein structure homology-modeling sever SWISS-MODEL20. FF was docked into the P. falciparum ProRS active site based on the structure of ProRS:halofuginone:ATPa complex, while ATP was docked based on the structure of the T. thermophilus ProRS:tRNA:ATP complex (PDB code 1H4Q).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569068&req=5

Figure 4: FF blocks ProRSFebrifugine (FF) docked to the active site of P. falcipaurm ProRS (UniProtKB code Q8I5R7). ProRS and FF are colored as cyan and yellow, respectively. The hydrogen bonds are indicated with dashes. The P. falciparum ProRS structure was generated by the protein structure homology-modeling sever SWISS-MODEL20. FF was docked into the P. falciparum ProRS active site based on the structure of ProRS:halofuginone:ATPa complex, while ATP was docked based on the structure of the T. thermophilus ProRS:tRNA:ATP complex (PDB code 1H4Q).
Mentions: HF is a halogenated derivative of febrifugine, which is the bioactive constituent in the Chang Shan herb that has long been used to treat malaria. The human and malaria parasite P. falciparum ProRS binding sites are highly conversed (Supplementary Fig. 4). With that in mind, using our ATP-dependent docking of HF to human ProRS as a template, we were able to show the potential for docking of FF to P. falcipaurm ProRS (Fig. 4). Thus, our analysis suggests malarial ProRS may also be the target of FF. This possibility could also explain why the killing effect of FF on P. falciparum in culture is reversed by proline8.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: The Skaggs Institute for Chemical Biology, Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

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.

Show MeSH
Related in: MedlinePlus