5j58

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<StructureSection load='5j58' size='340' side='right'caption='[[5j58]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
<StructureSection load='5j58' size='340' side='right'caption='[[5j58]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5j58]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Tryb2 Tryb2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J58 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5J58 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5j58]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei_brucei_TREU927 Trypanosoma brucei brucei TREU927]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J58 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5J58 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MET:METHIONINE'>MET</scene>, <scene name='pdbligand=N56:(3S)-1-(5-CHLORO-1H-IMIDAZO[4,5-B]PYRIDIN-2-YL)-N-[(3,5-DICHLOROPHENYL)METHYL]PIPERIDIN-3-AMINE'>N56</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Tb10.70.6470 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=185431 TRYB2])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MET:METHIONINE'>MET</scene>, <scene name='pdbligand=N56:(3S)-1-(5-CHLORO-1H-IMIDAZO[4,5-B]PYRIDIN-2-YL)-N-[(3,5-DICHLOROPHENYL)METHYL]PIPERIDIN-3-AMINE'>N56</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'>[https://proteopedia.org/fgij/fg.htm?mol=5j58 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j58 OCA], [https://pdbe.org/5j58 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5j58 RCSB], [https://www.ebi.ac.uk/pdbsum/5j58 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5j58 ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5j58 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j58 OCA], [http://pdbe.org/5j58 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j58 RCSB], [http://www.ebi.ac.uk/pdbsum/5j58 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j58 ProSAT]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/Q38C91_TRYB2 Q38C91_TRYB2]
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A screening hit 1 against Trypanosoma brucei methionyl-tRNA synthetase was optimized using a structure-guided approach. The optimization led to the identification of two novel series of potent inhibitors, the cyclic linker and linear linker series. Compounds of both series were potent in a T. brucei growth inhibition assay while showing low toxicity to mammalian cells. The best compound of each series, 16 and 31, exhibited EC50s of 39 and 22 nM, respectively. Compounds 16 and 31 also exhibited promising PK properties after oral dosing in mice. Moreover, compound 31 had moderately good brain permeability, with a brain/plasma ratio of 0.27 at 60 min after IP injection. This study provides new lead compounds for arriving at new treatments of human African trypanosomiasis (HAT).
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Structure-guided design of novel Trypanosoma brucei Methionyl-tRNA synthetase inhibitors.,Huang W, Zhang Z, Barros-Alvarez X, Koh CY, Ranade RM, Gillespie JR, Creason SA, Shibata S, Verlinde CL, Hol WG, Buckner FS, Fan E Eur J Med Chem. 2016 Nov 29;124:1081-1092. doi: 10.1016/j.ejmech.2016.10.024., Epub 2016 Oct 14. PMID:27788467<ref>PMID:27788467</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5j58" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Methionine--tRNA ligase]]
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[[Category: Trypanosoma brucei brucei TREU927]]
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[[Category: Tryb2]]
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[[Category: Barros-Alvarez X]]
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[[Category: Barros-Alvarez, X]]
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[[Category: Hol WGJ]]
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[[Category: Hol, W G.J]]
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[[Category: Inhibitor]]
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[[Category: Ligase]]
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[[Category: Ligase-ligase inhibitor complex]]
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[[Category: Methionine]]
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[[Category: Synthetase]]
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Current revision

Trypanosoma brucei methionyl-tRNA synthetase in complex with inhibitor (Chem 1856)

PDB ID 5j58

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