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==Trypanosoma brucei methionyl-tRNA synthetase in complex with inhibitor (Chem 1917)== | |||
<StructureSection load='5v49' size='340' side='right' caption='[[5v49]], [[Resolution|resolution]] 2.30Å' scene=''> | |||
== Structural highlights == | |||
<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> | |||
</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> | |||
<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> | |||
<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> | |||
<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> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5v49" style="background-color:#fffaf0;"></div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Methionine--tRNA ligase]] | |||
[[Category: Tryb2]] | |||
[[Category: Barros-Alvarez, X]] | [[Category: Barros-Alvarez, X]] | ||
[[Category: Hol, W G.J]] | |||
[[Category: Inhibitor]] | |||
[[Category: Ligase]] | |||
[[Category: Ligase-ligase inhibitor complex]] | |||
[[Category: Methionine]] | |||
[[Category: Synthetase]] | |||
Revision as of 04:52, 16 November 2017
Trypanosoma brucei methionyl-tRNA synthetase in complex with inhibitor (Chem 1917)
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