View source for 4mw9


==Trypanosoma brucei methionyl-tRNA synthetase in complex with inhibitor 1-{3-[(3-ethynylbenzyl)amino]propyl}-3-thiophen-3-ylurea (Chem 1478)==
<StructureSection load='4mw9' size='340' side='right'caption='[[4mw9]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4mw9]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei Trypanosoma brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MW9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MW9 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.65&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2EJ:1-{3-[(3-ETHYNYLBENZYL)AMINO]PROPYL}-3-THIOPHEN-3-YLUREA'>2EJ</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4mw9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mw9 OCA], [https://pdbe.org/4mw9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mw9 RCSB], [https://www.ebi.ac.uk/pdbsum/4mw9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mw9 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q38C91_TRYB2 Q38C91_TRYB2] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Methionyl-tRNA synthetase of Trypanosoma brucei (TbMetRS) is an important target in the development of new antitrypanosomal drugs. The enzyme is essential, highly flexible and displaying a large degree of changes in protein domains and binding pockets in the presence of substrate, product and inhibitors. Targeting this protein will benefit from a profound understanding of how its structure adapts to ligand binding. A series of urea-based inhibitors (UBIs) has been developed with IC50 values as low as 19 nM against the enzyme. The UBIs were shown to be orally available and permeable through the blood-brain barrier, and are therefore candidates for development of drugs for the treatment of late stage human African trypanosomiasis. Here, we expand the structural diversity of inhibitors from the previously reported collection and tested for their inhibitory effect on TbMetRS and on the growth of T. brucei cells. The binding modes and binding pockets of 14 UBIs are revealed by determination of their crystal structures in complex with TbMetRS at resolutions between 2.2 A to 2.9 A. The structures show binding of the UBIs through conformational selection, including occupancy of the enlarged methionine pocket and the auxiliary pocket. General principles underlying the affinity of UBIs for TbMetRS are derived from these structures, in particular the optimum way to fill the two binding pockets. The conserved auxiliary pocket might play a role in binding tRNA. In addition, a crystal structure of a ternary TbMetRS*inhibitor*AMPPCP complex indicates that the UBIs are not competing with ATP for binding, instead are interacting with ATP through hydrogen bond. This suggests a possibility that a general 'ATP-engaging' binding mode can be utilized for the design and development of inhibitors targeting tRNA synthetases of other disease-causing pathogen.

Structures of Trypanosoma brucei Methionyl-tRNA Synthetase with Urea-Based Inhibitors Provide Guidance for Drug Design against Sleeping Sickness.,Koh CY, Kim JE, Wetzel AB, de van der Schueren WJ, Shibata S, Ranade RM, Liu J, Zhang Z, Gillespie JR, Buckner FS, Verlinde CL, Fan E, Hol WG PLoS Negl Trop Dis. 2014 Apr 17;8(4):e2775. doi: 10.1371/journal.pntd.0002775., eCollection 2014 Apr. PMID:24743796<ref>PMID:24743796</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4mw9" style="background-color:#fffaf0;"></div>

==See Also==
*[[Aminoacyl tRNA synthetase 3D structures|Aminoacyl tRNA synthetase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Trypanosoma brucei]]
[[Category: Fan E]]
[[Category: Hol WGJ]]
[[Category: Kim JE]]
[[Category: Koh CY]]
[[Category: Liu J]]
[[Category: Shibata S]]
[[Category: Verlinde CLMJ]]
[[Category: Wetzel AB]]
[[Category: Zhang Z]]
[[Category: De van der Schueren WJ]]