5v49

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==Trypanosoma brucei methionyl-tRNA synthetase in complex with inhibitor (Chem 1917)==
==Trypanosoma brucei methionyl-tRNA synthetase in complex with inhibitor (Chem 1917)==
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<StructureSection load='5v49' size='340' side='right' caption='[[5v49]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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<StructureSection load='5v49' size='340' side='right'caption='[[5v49]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5v49]] 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=5V49 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5V49 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5v49]] 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=5V49 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5V49 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=8WA:N~1~-(5-chloro-1H-imidazo[4,5-b]pyridin-2-yl)-N~2~-[(4R)-6,8-dichloro-1,2,3,4-tetrahydroquinolin-4-yl]-N~1~-methylethane-1,2-diamine'>8WA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MET:METHIONINE'>MET</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]] 2.3&#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=8WA:N~1~-(5-chloro-1H-imidazo[4,5-b]pyridin-2-yl)-N~2~-[(4R)-6,8-dichloro-1,2,3,4-tetrahydroquinolin-4-yl]-N~1~-methylethane-1,2-diamine'>8WA</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'>[https://proteopedia.org/fgij/fg.htm?mol=5v49 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v49 OCA], [https://pdbe.org/5v49 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5v49 RCSB], [https://www.ebi.ac.uk/pdbsum/5v49 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5v49 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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5v49 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v49 OCA], [http://pdbe.org/5v49 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5v49 RCSB], [http://www.ebi.ac.uk/pdbsum/5v49 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5v49 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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Potent inhibitors of Trypanosoma brucei methionyl-tRNA synthetase were previously designed using a structure-guided approach. Compounds 1 and 2 were the most active compounds in the cyclic and linear linker series, respectively. To further improve cellular potency, SAR investigation of a binding fragment targeting the "enlarged methionine pocket" (EMP) was performed. The optimization led to the identification of a 6,8-dichloro-tetrahydroquinoline ring as a favorable fragment to bind the EMP. Replacement of 3,5-dichloro-benzyl group (the EMP binding fragment) of inhibitor 2 using this tetrahydroquinoline fragment resulted in compound 13, that exhibited an EC50 of 4nM.
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Optimization of a binding fragment targeting the "enlarged methionine pocket" leads to potent Trypanosoma brucei methionyl-tRNA synthetase inhibitors.,Huang W, Zhang Z, Ranade RM, Gillespie JR, Barros-Alvarez X, Creason SA, Shibata S, Verlinde CLMJ, Hol WGJ, Buckner FS, Fan E Bioorg Med Chem Lett. 2017 Jun 15;27(12):2702-2707. doi:, 10.1016/j.bmcl.2017.04.048. Epub 2017 Apr 17. PMID:28465105<ref>PMID:28465105</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 5v49" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Methionine--tRNA ligase]]
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[[Category: Large Structures]]
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[[Category: Tryb2]]
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[[Category: Trypanosoma brucei brucei TREU927]]
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[[Category: Barros-Alvarez, X]]
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[[Category: Barros-Alvarez X]]
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[[Category: Hol, W G.J]]
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[[Category: Hol WGJ]]
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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 1917)

PDB ID 5v49

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