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| | ==Crystal Structure of Prolyl-tRNA synthetase (ProRS, Proline--tRNA ligase) from Plasmodium falciparum in complex with TCMDC-124506== | | ==Crystal Structure of Prolyl-tRNA synthetase (ProRS, Proline--tRNA ligase) from Plasmodium falciparum in complex with TCMDC-124506== |
| - | <StructureSection load='4wi1' size='340' side='right' caption='[[4wi1]], [[Resolution|resolution]] 1.65Å' scene=''> | + | <StructureSection load='4wi1' size='340' side='right'caption='[[4wi1]], [[Resolution|resolution]] 1.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4wi1]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Plaf7 Plaf7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WI1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WI1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4wi1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WI1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WI1 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3O6:1-(4-FLUOROPHENYL)-3-[4-(4-FLUOROPHENYL)-1-METHYL-3-(TRIFLUOROMETHYL)-1H-PYRAZOL-5-YL]UREA'>3O6</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 1.65Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ncx|4ncx]], [[4olf|4olf]], [[4q15|4q15]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3O6:1-(4-FLUOROPHENYL)-3-[4-(4-FLUOROPHENYL)-1-METHYL-3-(TRIFLUOROMETHYL)-1H-PYRAZOL-5-YL]UREA'>3O6</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">proRS, PFL0670c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=36329 PLAF7])</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=4wi1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wi1 OCA], [https://pdbe.org/4wi1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wi1 RCSB], [https://www.ebi.ac.uk/pdbsum/4wi1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wi1 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Proline--tRNA_ligase Proline--tRNA ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.1.1.15 6.1.1.15] </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=4wi1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wi1 OCA], [http://pdbe.org/4wi1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wi1 RCSB], [http://www.ebi.ac.uk/pdbsum/4wi1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4wi1 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/SYP_PLAF7 SYP_PLAF7]] Catalyzes the attachment of proline to tRNA(Pro) in a two-step reaction: proline is first activated by ATP to form Pro-AMP and then transferred to the acceptor end of tRNA(Pro) (By similarity). Functions in trans to edit the amino acid moiety from incorrectly charged Ala-tRNA(Pro). Has no activity on correctly charged Pro-tRNA(Pro) or Ala-tRNA(Ala).<ref>PMID:14663147</ref> | + | [https://www.uniprot.org/uniprot/SYP_PLAF7 SYP_PLAF7] Catalyzes the attachment of proline to tRNA(Pro) in a two-step reaction: proline is first activated by ATP to form Pro-AMP and then transferred to the acceptor end of tRNA(Pro) (By similarity). Functions in trans to edit the amino acid moiety from incorrectly charged Ala-tRNA(Pro). Has no activity on correctly charged Pro-tRNA(Pro) or Ala-tRNA(Ala).<ref>PMID:14663147</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 4wi1" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4wi1" 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: Plaf7]] | + | [[Category: Large Structures]] |
| - | [[Category: Proline--tRNA ligase]]
| + | [[Category: Plasmodium falciparum 3D7]] |
| - | [[Category: Structural genomic]]
| + | |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: Plasmodium falciparum]] | + | |
| - | [[Category: Proline--trna ligase]]
| + | |
| - | [[Category: Prolyl-trna synthetase]]
| + | |
| - | [[Category: Pror]]
| + | |
| - | [[Category: Ssgcid]]
| + | |
| Structural highlights
4wi1 is a 2 chain structure with sequence from Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.65Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
SYP_PLAF7 Catalyzes the attachment of proline to tRNA(Pro) in a two-step reaction: proline is first activated by ATP to form Pro-AMP and then transferred to the acceptor end of tRNA(Pro) (By similarity). Functions in trans to edit the amino acid moiety from incorrectly charged Ala-tRNA(Pro). Has no activity on correctly charged Pro-tRNA(Pro) or Ala-tRNA(Ala).[1]
Publication Abstract from PubMed
Plasmodium falciparum (Pf) prolyl-tRNA synthetase (ProRS) is one of the few chemical-genetically validated drug targets for malaria, yet highly selective inhibitors have not been described. In this paper, approximately 40,000 compounds were screened to identify compounds that selectively inhibit PfProRS enzyme activity vs. H. sapiens (Hs) ProRS. X-ray crystallography structures were solved for apo, as well as substrate, and inhibitor bound forms of PfProRS. We identified two new inhibitors of PfProRS that bind outside the active site. These two allosteric inhibitors showed >100X specificity for PfProRS compared to HsProRS, demonstrating this class of compounds could overcome the toxicity related to HsProRS inhibition by halofuginone and its analogs. Initial medicinal chemistry was performed on one of the two compounds, guided by the co-crystallography of the compound with PfProRS, and the results can instruct future medicinal chemistry work to optimize these promising new leads for drug development against malaria.
Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase.,Nakazawa Hewitt S, Dranow DM, Horst BG, Abendroth JA, Forte B, Hallyburton I, Jansen C, Baragana B, Choi R, Rivas KL, Hulverson MA, Dumais M, Edwards TE, Lorimer DD, Fairlamb AH, Gray DW, Read KD, Lehane AM, Kirk K, Myler PJ, Wernimont A, Walpole CS, Stacy R, Barrett LK, Gilbert IH, Van Voorhis WC ACS Infect Dis. 2016 Oct 31. PMID:27798837[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ahel I, Korencic D, Ibba M, Soll D. Trans-editing of mischarged tRNAs. Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15422-7. Epub 2003 Dec 8. PMID:14663147 doi:http://dx.doi.org/10.1073/pnas.2136934100
- ↑ Nakazawa Hewitt S, Dranow DM, Horst BG, Abendroth JA, Forte B, Hallyburton I, Jansen C, Baragana B, Choi R, Rivas KL, Hulverson MA, Dumais M, Edwards TE, Lorimer DD, Fairlamb AH, Gray DW, Read KD, Lehane AM, Kirk K, Myler PJ, Wernimont A, Walpole CS, Stacy R, Barrett LK, Gilbert IH, Van Voorhis WC. Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase. ACS Infect Dis. 2016 Oct 31. PMID:27798837 doi:http://dx.doi.org/10.1021/acsinfecdis.6b00078
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