View source for 6w29


==Trypanosoma cruzi Malic Enzyme in complex with inhibitor (MEC013)==
<StructureSection load='6w29' size='340' side='right'caption='[[6w29]], [[Resolution|resolution]] 2.14&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6w29]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_cruzi_strain_CL_Brener Trypanosoma cruzi strain CL Brener]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W29 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6W29 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]] 2.14&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=SEV:3,5-bis(fluoranyl)-~{N}-[3-[(4-methoxyphenyl)sulfamoyl]phenyl]benzamide'>SEV</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=6w29 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w29 OCA], [https://pdbe.org/6w29 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w29 RCSB], [https://www.ebi.ac.uk/pdbsum/6w29 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w29 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q4DJ68_TRYCC Q4DJ68_TRYCC] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Chagas disease, an infectious condition caused by Trypanosoma cruzi, lacks treatment with drugs with desired efficacy and safety profiles. To address this unmet medical need, a set of trypanocidal compounds were identified through a large multicenter phenotypic-screening initiative and assembled in the GSK Chagas Box. In the present work, we report the screening of the Chagas Box against T. cruzi malic enzymes (MEs) and the identification of three potent inhibitors of its cytosolic isoform (TcMEc). One of these compounds, TCMDC-143108 (1), came out as a nanomolar inhibitor of TcMEc, and 14 new derivatives were synthesized and tested for target inhibition and efficacy against the parasite. Moreover, we determined the crystallographic structures of TcMEc in complex with TCMDC-143108 (1) and six derivatives, revealing the allosteric inhibition site and the determinants of specificity. Our findings connect phenotypic hits from the Chagas Box to a relevant metabolic target in the parasite, providing data to foster new structure-activity guided hit optimization initiatives.

Trypanosoma cruzi Malic Enzyme Is the Target for Sulfonamide Hits from the GSK Chagas Box.,Mercaldi GF, Eufrasio AG, Ranzani AT, do Nascimento Faria J, Mota SGR, Fagundes M, Bruder M, Cordeiro AT ACS Infect Dis. 2021 Jul 19. doi: 10.1021/acsinfecdis.1c00231. PMID:34279922<ref>PMID:34279922</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6w29" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Trypanosoma cruzi strain CL Brener]]
[[Category: Cordeiro AT]]
[[Category: Fagundes M]]
[[Category: Faria JN]]
[[Category: Mercaldi GF]]