5nfh

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'''Unreleased structure'''
 
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The entry 5nfh is ON HOLD until Paper Publication
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==Trypanosoma brucei methionyl-tRNA synthetase in complex with a quinazolinone inhibitor==
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<StructureSection load='5nfh' size='340' side='right' caption='[[5nfh]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[5nfh]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NFH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NFH FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8W2:2-[3-[[4,6-bis(chloranyl)-1~{H}-indol-2-yl]methylamino]propylamino]-3~{H}-quinazolin-4-one'>8W2</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MET:METHIONINE'>MET</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Methionine--tRNA_ligase Methionine--tRNA ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.1.1.10 6.1.1.10] </span></td></tr>
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<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=5nfh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nfh OCA], [http://pdbe.org/5nfh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nfh RCSB], [http://www.ebi.ac.uk/pdbsum/5nfh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nfh ProSAT]</span></td></tr>
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</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Methionyl-tRNA synthetase (MetRS) has been chemically validated as a drug target in the kinetoplastid parasite Trypanosoma brucei. In the present study, we investigate the validity of this target in the related trypanosomatid Leishmania donovani. Following development of a robust high-throughput compatible biochemical assay, a compound screen identified DDD806905 as a highly potent inhibitor of LdMetRS (Ki of 18 nM). Crystallography revealed this compound binds to the methionine pocket of MetRS with enzymatic studies confirming DDD806905 displays competitive inhibition with respect to methionine and mixed inhibition with respect to ATP binding. DDD806905 showed activity, albeit with different levels of potency, in various Leishmania cell-based viability assays, with on-target activity observed in both Leishmania promastigote cell assays and a Leishmania tarentolae in vitro translation assay. Unfortunately, this compound failed to show efficacy in an animal model of leishmaniasis. We investigated the potential causes for the discrepancies in activity observed in different Leishmania cell assays and the lack of efficacy in the animal model and found that high protein binding as well as sequestration of this dibasic compound into acidic compartments may play a role. Despite medicinal chemistry efforts to address the dibasic nature of DDD806905 and analogues, no progress could be achieved with the current chemical series. Although DDD806905 is not a developable antileishmanial compound, MetRS remains an attractive antileishmanial drug target.
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Authors: Robinson, D.A., Eadsforth, T.C., Shepherd, S.M., Torrie, L.S., De Rycker, M., Gilbert, I.H.
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Chemical Validation of Methionyl-tRNA Synthetase as a Druggable Target in Leishmania donovani.,Torrie LS, Brand S, Robinson DA, Ko EJ, Stojanovski L, Simeons FRC, Wyllie S, Thomas J, Ellis L, Osuna-Cabello M, Epemolu O, Nuhs A, Riley J, MacLean L, Manthri S, Read KD, Gilbert IH, Fairlamb AH, De Rycker M ACS Infect Dis. 2017 Oct 2. doi: 10.1021/acsinfecdis.7b00047. PMID:28967262<ref>PMID:28967262</ref>
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Description: Trypanosoma brucei methionyl-tRNA synthetase in complex with a quinazolinone inhibitor
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Robinson, D.A]]
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<div class="pdbe-citations 5nfh" style="background-color:#fffaf0;"></div>
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[[Category: De Rycker, M]]
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== References ==
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[[Category: Shepherd, S.M]]
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<references/>
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[[Category: Torrie, L.S]]
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__TOC__
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[[Category: Gilbert, I.H]]
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</StructureSection>
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[[Category: Eadsforth, T.C]]
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[[Category: Methionine--tRNA ligase]]
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[[Category: Eadsforth, T C]]
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[[Category: Gilbert, I H]]
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[[Category: Robinson, D A]]
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[[Category: Rycker, M De]]
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[[Category: Shepherd, S M]]
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[[Category: Torrie, L S]]
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[[Category: Complex]]
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[[Category: Drug discovery]]
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[[Category: Inhibitor]]
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[[Category: Ligase]]
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[[Category: Ligase-ligase inhibitor]]
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[[Category: Methionine]]
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[[Category: Synthetase]]

Revision as of 06:59, 11 October 2017

Trypanosoma brucei methionyl-tRNA synthetase in complex with a quinazolinone inhibitor

5nfh, resolution 2.80Å

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