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| | ==Crystal structure of human prolyl-tRNA synthetase in complex with halofuginone and ATP analogue== | | ==Crystal structure of human prolyl-tRNA synthetase in complex with halofuginone and ATP analogue== |
| - | <StructureSection load='4hvc' size='340' side='right' caption='[[4hvc]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='4hvc' size='340' side='right'caption='[[4hvc]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4hvc]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HVC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HVC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4hvc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HVC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HVC FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=HFG:7-BROMO-6-CHLORO-3-{3-[(2R,3S)-3-HYDROXYPIPERIDIN-2-YL]-2-OXOPROPYL}QUINAZOLIN-4(3H)-ONE'>HFG</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=HFG:7-BROMO-6-CHLORO-3-{3-[(2R,3S)-3-HYDROXYPIPERIDIN-2-YL]-2-OXOPROPYL}QUINAZOLIN-4(3H)-ONE'>HFG</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EPRS, GLNS, PARS, QARS, QPRS, PIG32 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4hvc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hvc OCA], [https://pdbe.org/4hvc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hvc RCSB], [https://www.ebi.ac.uk/pdbsum/4hvc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hvc ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4hvc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hvc OCA], [http://pdbe.org/4hvc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4hvc RCSB], [http://www.ebi.ac.uk/pdbsum/4hvc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4hvc ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/SYEP_HUMAN SYEP_HUMAN]] Catalyzes the attachment of the cognate amino acid to the corresponding tRNA in a two-step reaction: the amino acid is first activated by ATP to form a covalent intermediate with AMP and is then transferred to the acceptor end of the cognate tRNA. Component of the GAIT (gamma interferon-activated inhibitor of translation) complex which mediates interferon-gamma-induced transcript-selective translation inhibition in inflammation processes. Upon interferon-gamma activation and subsequent phosphorylation dissociates from the multisynthetase complex and assembles into the GAIT complex which binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin) and suppresses their translation.<ref>PMID:1756734</ref> <ref>PMID:15479637</ref> <ref>PMID:23071094</ref> | + | [https://www.uniprot.org/uniprot/SYEP_HUMAN SYEP_HUMAN] Catalyzes the attachment of the cognate amino acid to the corresponding tRNA in a two-step reaction: the amino acid is first activated by ATP to form a covalent intermediate with AMP and is then transferred to the acceptor end of the cognate tRNA. Component of the GAIT (gamma interferon-activated inhibitor of translation) complex which mediates interferon-gamma-induced transcript-selective translation inhibition in inflammation processes. Upon interferon-gamma activation and subsequent phosphorylation dissociates from the multisynthetase complex and assembles into the GAIT complex which binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin) and suppresses their translation.<ref>PMID:1756734</ref> <ref>PMID:15479637</ref> <ref>PMID:23071094</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4hvc" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4hvc" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Aminoacyl tRNA synthetase 3D structures|Aminoacyl tRNA synthetase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Schimmel, P]] | + | [[Category: Large Structures]] |
| - | [[Category: Sun, L]] | + | [[Category: Schimmel P]] |
| - | [[Category: Yang, X L]] | + | [[Category: Sun L]] |
| - | [[Category: Zhou, H]] | + | [[Category: Yang XL]] |
| - | [[Category: Ligase]] | + | [[Category: Zhou H]] |
| - | [[Category: Ligase-ligase inhibitor complex]]
| + | |
| Structural highlights
Function
SYEP_HUMAN Catalyzes the attachment of the cognate amino acid to the corresponding tRNA in a two-step reaction: the amino acid is first activated by ATP to form a covalent intermediate with AMP and is then transferred to the acceptor end of the cognate tRNA. Component of the GAIT (gamma interferon-activated inhibitor of translation) complex which mediates interferon-gamma-induced transcript-selective translation inhibition in inflammation processes. Upon interferon-gamma activation and subsequent phosphorylation dissociates from the multisynthetase complex and assembles into the GAIT complex which binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin) and suppresses their translation.[1] [2] [3]
Publication Abstract from PubMed
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.
ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase.,Zhou H, Sun L, Yang XL, Schimmel P Nature. 2012 Dec 23. doi: 10.1038/nature11774. PMID:23263184[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Cerini C, Kerjan P, Astier M, Gratecos D, Mirande M, Semeriva M. A component of the multisynthetase complex is a multifunctional aminoacyl-tRNA synthetase. EMBO J. 1991 Dec;10(13):4267-77. PMID:1756734
- ↑ Sampath P, Mazumder B, Seshadri V, Gerber CA, Chavatte L, Kinter M, Ting SM, Dignam JD, Kim S, Driscoll DM, Fox PL. Noncanonical function of glutamyl-prolyl-tRNA synthetase: gene-specific silencing of translation. Cell. 2004 Oct 15;119(2):195-208. PMID:15479637 doi:http://dx.doi.org/10.1016/j.cell.2004.09.030
- ↑ Arif A, Chatterjee P, Moodt RA, Fox PL. Heterotrimeric GAIT complex drives transcript-selective translation inhibition in murine macrophages. Mol Cell Biol. 2012 Dec;32(24):5046-55. doi: 10.1128/MCB.01168-12. Epub 2012 Oct , 15. PMID:23071094 doi:10.1128/MCB.01168-12
- ↑ Zhou H, Sun L, Yang XL, Schimmel P. ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase. Nature. 2012 Dec 23. doi: 10.1038/nature11774. PMID:23263184 doi:http://dx.doi.org/10.1038/nature11774
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