View source for 4yrc


==Crystal structure of T. cruzi Histidyl-tRNA synthetase in complex with 2-aminoquinolin-8-ol (Chem 89)==
<StructureSection load='4yrc' size='340' side='right' caption='[[4yrc]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4yrc]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Trycc Trycc]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YRC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YRC FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0P6:2-AMINOQUINOLIN-8-OL'>0P6</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=HIS:HISTIDINE'>HIS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4yp0|4yp0]], [[4ypf|4ypf]], [[4yre|4yre]], [[4yrf|4yrf]], [[4yrg|4yrg]], [[4yri|4yri]], [[4yrj|4yrj]], [[4yrk|4yrk]], [[4yrl|4yrl]], [[4yrm|4yrm]], [[4yrn|4yrn]], [[4yro|4yro]], [[4yrp|4yrp]], [[4yrq|4yrq]], [[4yrr|4yrr]], [[4yrs|4yrs]], [[4yrt|4yrt]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Tc00.1047053507019.40 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=353153 TRYCC])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histidine--tRNA_ligase Histidine--tRNA ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.1.1.21 6.1.1.21] </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=4yrc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yrc OCA], [http://pdbe.org/4yrc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4yrc RCSB], [http://www.ebi.ac.uk/pdbsum/4yrc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4yrc ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
American trypanosomiasis, commonly known as Chagas disease, is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. The chronic form of the infection often causes debilitating morbidity and mortality. However, the current treatment for the disease is typically inadequate owing to drug toxicity and poor efficacy, necessitating a continual effort to discover and develop new antiparasitic therapeutic agents. The structure of T. cruzi histidyl-tRNA synthetase (HisRS), a validated drug target, has previously been reported. Based on this structure and those of human cytosolic HisRS, opportunities for the development of specific inhibitors were identified. Here, efforts are reported to identify small molecules that bind to T. cruzi HisRS through fragment-based crystallographic screening in order to arrive at chemical starting points for the development of specific inhibitors. T. cruzi HisRS was soaked into 68 different cocktails from the Medical Structural Genomics of Pathogenic Protozoa (MSGPP) fragment library and diffraction data were collected to identify bound fragments after soaking. A total of 15 fragments were identified, all bound to the same site on the protein, revealing a fragment-binding hotspot adjacent to the ATP-binding pocket. On the basis of the initial hits, the design of reactive fragments targeting the hotspot which would be simultaneously covalently linked to a cysteine residue present only in trypanosomatid HisRS was initiated. Inhibition of T. cruzi HisRS was observed with the resultant reactive fragments and the anticipated binding mode was confirmed crystallographically. These results form a platform for the development of future generations of selective inhibitors for trypanosomatid HisRS.

A binding hotspot in Trypanosoma cruzi histidyl-tRNA synthetase revealed by fragment-based crystallographic cocktail screens.,Koh CY, Kallur Siddaramaiah L, Ranade RM, Nguyen J, Jian T, Zhang Z, Gillespie JR, Buckner FS, Verlinde CL, Fan E, Hol WG Acta Crystallogr D Biol Crystallogr. 2015 Aug 1;71(Pt 8):1684-98. doi:, 10.1107/S1399004715007683. Epub 2015 Jul 31. PMID:26249349<ref>PMID:26249349</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4yrc" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Histidine--tRNA ligase]]
[[Category: Trycc]]
[[Category: Hol, W G.J]]
[[Category: Koh, C Y]]
[[Category: Aar]]
[[Category: Aminoacyl-trna synthetase]]
[[Category: Hisr]]
[[Category: Ligase]]
[[Category: Ligase-ligase inhibitor complex]]
[[Category: Protein-inhibitor complex]]
[[Category: Trypanosoma cruzi]]