Publication Date:
2012-12-25
Description:
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 A 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569068/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569068/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Huihao -- Sun, Litao -- Yang, Xiang-Lei -- Schimmel, Paul -- GM15539/GM/NIGMS NIH HHS/ -- GM23562/GM/NIGMS NIH HHS/ -- GM88278/GM/NIGMS NIH HHS/ -- R01 GM088278/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Feb 7;494(7435):121-4. doi: 10.1038/nature11774. Epub 2012 Dec 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Skaggs Institute for Chemical Biology, Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23263184" target="_blank"〉PubMed〈/a〉
Keywords:
Adenosine Triphosphate/chemistry/*metabolism/pharmacology
;
Amino Acyl-tRNA Synthetases/antagonists & inhibitors/*chemistry/*metabolism
;
Antimalarials/chemistry/pharmacology
;
Binding Sites
;
Crystallography, X-Ray
;
Herbal Medicine
;
Humans
;
Hydrogen Bonding
;
Hydrophobic and Hydrophilic Interactions
;
Ligands
;
Medicine, Chinese Traditional
;
Models, Molecular
;
Piperidines/*chemistry/*metabolism/pharmacology
;
Proline/chemistry/metabolism
;
Quinazolines/chemistry/pharmacology
;
Quinazolinones/*chemistry/*metabolism/pharmacology
;
RNA, Transfer/chemistry/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
