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| | ==Crystal structure of human Prolyl-tRNA synthetase (PRS) in complex with inhibitor== | | ==Crystal structure of human Prolyl-tRNA synthetase (PRS) in complex with inhibitor== |
| - | <StructureSection load='5vad' size='340' side='right' caption='[[5vad]], [[Resolution|resolution]] 2.36Å' scene=''> | + | <StructureSection load='5vad' size='340' side='right'caption='[[5vad]], [[Resolution|resolution]] 2.36Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5vad]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VAD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VAD FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5vad]] 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=5VAD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5VAD FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=91Y:3-[(cyclohexanecarbonyl)amino]-N-(2,3-dihydro-1H-inden-2-yl)pyrazine-2-carboxamide'>91Y</scene>, <scene name='pdbligand=PRO:PROLINE'>PRO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.36Å</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=5vad FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vad OCA], [http://pdbe.org/5vad PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vad RCSB], [http://www.ebi.ac.uk/pdbsum/5vad PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vad ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=91Y:3-[(cyclohexanecarbonyl)amino]-N-(2,3-dihydro-1H-inden-2-yl)pyrazine-2-carboxamide'>91Y</scene>, <scene name='pdbligand=PRO:PROLINE'>PRO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=5vad FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vad OCA], [https://pdbe.org/5vad PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5vad RCSB], [https://www.ebi.ac.uk/pdbsum/5vad PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5vad 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 5vad" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5vad" 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: Okada, K]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Skene, R J]] | + | [[Category: Large Structures]] |
| - | [[Category: Aminoacyl-trna synthetase]] | + | [[Category: Okada K]] |
| - | [[Category: Atp dependent]] | + | [[Category: Skene RJ]] |
| - | [[Category: Inhibitor]]
| + | |
| - | [[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
Prolyl-tRNA synthetase (PRS) is a member of the aminoacyl-tRNA synthetase family of enzymes and catalyzes the synthesis of prolyl-tRNAPro using ATP, l-proline, and tRNAPro as substrates. An ATP-dependent PRS inhibitor, halofuginone, was shown to suppress autoimmune responses, suggesting that the inhibition of PRS is a potential therapeutic approach for inflammatory diseases. Although a few PRS inhibitors have been derivatized from natural sources or substrate mimetics, small-molecule human PRS inhibitors have not been reported. In this study, we discovered a novel series of pyrazinamide PRS inhibitors from a compound library using pre-transfer editing activity of human PRS enzyme. Steady-state biochemical analysis on the inhibitory mode revealed its distinctive characteristics of inhibition with proline uncompetition and ATP competition. The binding activity of a representative compound was time-dependently potentiated by the presence of l-proline with Kd of 0.76 nM. Thermal shift assays demonstrated the stabilization of PRS in complex with l-proline and pyrazinamide PRS inhibitors. The binding mode of the PRS inhibitor to the ATP site of PRS enzyme was elucidated using the ternary complex crystal structure with l-proline. The results demonstrated the different inhibitory and binding mode of pyrazinamide PRS inhibitors from preceding halofuginone. Furthermore, the PRS inhibitor inhibited intracellular protein synthesis via a different mode than halofuginone. In conclusion, we have identified a novel drug-like PRS inhibitor with a distinctive binding mode. This inhibitor was effective in a cellular context. Thus, the series of PRS inhibitors are considered to be applicable to further development with differentiation from preceding halofuginone.
Discovery of a novel prolyl-tRNA synthetase inhibitor and elucidation of its binding mode to the ATP site in complex with l-proline.,Adachi R, Okada K, Skene R, Ogawa K, Miwa M, Tsuchinaga K, Ohkubo S, Henta T, Kawamoto T Biochem Biophys Res Commun. 2017 Jun 24;488(2):393-399. doi:, 10.1016/j.bbrc.2017.05.064. Epub 2017 May 10. PMID:28501621[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
- ↑ Adachi R, Okada K, Skene R, Ogawa K, Miwa M, Tsuchinaga K, Ohkubo S, Henta T, Kawamoto T. Discovery of a novel prolyl-tRNA synthetase inhibitor and elucidation of its binding mode to the ATP site in complex with l-proline. Biochem Biophys Res Commun. 2017 Jun 24;488(2):393-399. doi:, 10.1016/j.bbrc.2017.05.064. Epub 2017 May 10. PMID:28501621 doi:http://dx.doi.org/10.1016/j.bbrc.2017.05.064
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