4q15
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
==Crystal Structure of Prolyl-tRNA synthetase (ProRS, Proline--tRNA ligase) from Plasmodium falciparum in complex with Halofuginone and AMPPNP in space group P212121 at 2.35 A== | ==Crystal Structure of Prolyl-tRNA synthetase (ProRS, Proline--tRNA ligase) from Plasmodium falciparum in complex with Halofuginone and AMPPNP in space group P212121 at 2.35 A== | ||
| - | <StructureSection load='4q15' size='340' side='right'caption='[[4q15]]' scene=''> | + | <StructureSection load='4q15' size='340' side='right'caption='[[4q15]], [[Resolution|resolution]] 2.35Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Q15 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Q15 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4q15]] 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=4Q15 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Q15 FirstGlance]. <br> |
| - | </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=4q15 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4q15 OCA], [https://pdbe.org/4q15 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4q15 RCSB], [https://www.ebi.ac.uk/pdbsum/4q15 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4q15 ProSAT]</span></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]] 2.35Å</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=EDO:1,2-ETHANEDIOL'>EDO</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></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=4q15 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4q15 OCA], [https://pdbe.org/4q15 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4q15 RCSB], [https://www.ebi.ac.uk/pdbsum/4q15 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4q15 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [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;"> | ||
| + | == 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<ref>PMID:27798837</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 4q15" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
*[[Aminoacyl tRNA synthetase 3D structures|Aminoacyl tRNA synthetase 3D structures]] | *[[Aminoacyl tRNA synthetase 3D structures|Aminoacyl tRNA synthetase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| + | [[Category: Plasmodium falciparum 3D7]] | ||
Current revision
Crystal Structure of Prolyl-tRNA synthetase (ProRS, Proline--tRNA ligase) from Plasmodium falciparum in complex with Halofuginone and AMPPNP in space group P212121 at 2.35 A
| |||||||||||
