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==Trypanosoma brucei methionyl-tRNA synthetase in complex with inhibitorN-(3,5-dichlorobenzyl)-2,2-difluoro-N'-(1H-imidazo[4,5-b]pyridin-2-yl)propane-1,3-diamine (Chem 1708)== | ==Trypanosoma brucei methionyl-tRNA synthetase in complex with inhibitorN-(3,5-dichlorobenzyl)-2,2-difluoro-N'-(1H-imidazo[4,5-b]pyridin-2-yl)propane-1,3-diamine (Chem 1708)== | ||
<StructureSection load='4zt4' size='340' side='right' caption='[[4zt4]], [[Resolution|resolution]] 2.30Å' scene=''> | <StructureSection load='4zt4' size='340' side='right'caption='[[4zt4]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4zt4]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZT4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZT4 FirstGlance]. <br> | <table><tr><td colspan='2'>[[4zt4]] 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=4ZT4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZT4 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4RO:N-(3,5-DICHLOROBENZYL)-2,2-DIFLUORO-N-(1H-IMIDAZO[4,5-B]PYRIDIN-2-YL)PROPANE-1,3-DIAMINE'>4RO</scene>, <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=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4RO:N-(3,5-DICHLOROBENZYL)-2,2-DIFLUORO-N-(1H-IMIDAZO[4,5-B]PYRIDIN-2-YL)PROPANE-1,3-DIAMINE'>4RO</scene>, <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=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CAS:S-(DIMETHYLARSENIC)CYSTEINE'>CAS</scene></td></tr> | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CAS:S-(DIMETHYLARSENIC)CYSTEINE'>CAS</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zt6|4zt6]], [[4zt5|4zt5]], [[4zt7|4zt7]], [[4zt3|4zt3]], [[4zt2|4zt2]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zt6|4zt6]], [[4zt5|4zt5]], [[4zt7|4zt7]], [[4zt3|4zt3]], [[4zt2|4zt2]]</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='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=4zt4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zt4 OCA], [http://pdbe.org/4zt4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zt4 RCSB], [http://www.ebi.ac.uk/pdbsum/4zt4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zt4 ProSAT]</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=4zt4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zt4 OCA], [http://pdbe.org/4zt4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zt4 RCSB], [http://www.ebi.ac.uk/pdbsum/4zt4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zt4 ProSAT]</span></td></tr> | ||
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</div> | </div> | ||
<div class="pdbe-citations 4zt4" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 4zt4" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Aminoacyl tRNA synthetase 3D structures|Aminoacyl tRNA synthetase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Methionine--tRNA ligase]] | [[Category: Methionine--tRNA ligase]] | ||
[[Category: Tryb2]] | |||
[[Category: Hol, W G.J]] | [[Category: Hol, W G.J]] | ||
[[Category: Koh, C Y]] | [[Category: Koh, C Y]] | ||
Revision as of 11:44, 26 June 2019
Trypanosoma brucei methionyl-tRNA synthetase in complex with inhibitorN-(3,5-dichlorobenzyl)-2,2-difluoro-N'-(1H-imidazo[4,5-b]pyridin-2-yl)propane-1,3-diamine (Chem 1708)Trypanosoma brucei methionyl-tRNA synthetase in complex with inhibitorN-(3,5-dichlorobenzyl)-2,2-difluoro-N'-(1H-imidazo[4,5-b]pyridin-2-yl)propane-1,3-diamine (Chem 1708)
Structural highlights
Publication Abstract from PubMedFluorination is a well-known strategy for improving the bioavailability of drug molecules. However, its impact on efficacy is not easily predicted. On the basis of inhibitor-bound protein crystal structures, we found a beneficial fluorination spot for inhibitors targeting methionyl-tRNA synthetase of Trypanosoma brucei. In particular, incorporating 5-fluoroimidazo[4,5-b]pyridine into inhibitors leads to central nervous system bioavailability and maintained or even improved efficacy. 5-Fluoroimidazo[4,5-b]pyridine Is a Privileged Fragment That Conveys Bioavailability to Potent Trypanosomal Methionyl-tRNA Synthetase Inhibitors.,Zhang Z, Koh CY, Ranade RM, Shibata S, Gillespie JR, Hulverson MA, Huang W, Nguyen J, Pendem N, Gelb MH, Verlinde CL, Hol WG, Buckner FS, Fan E ACS Infect Dis. 2016 Jun 10;2(6):399-404. doi: 10.1021/acsinfecdis.6b00036. Epub , 2016 Apr 11. PMID:27627628[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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