View source for 5duf


==Crystal structure of M. tuberculosis EchA6 bound to ligand GSK729A==
<StructureSection load='5duf' size='340' side='right'caption='[[5duf]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5duf]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DUF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DUF 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]] 1.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G7A:(5R,7S)-5-(4-ETHYLPHENYL)-7-(TRIFLUOROMETHYL)-4,5,6,7-TETRAHYDROPYRAZOLO[1,5-A]PYRIMIDINE-3-CARBOXYLIC+ACID'>G7A</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=5duf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5duf OCA], [https://pdbe.org/5duf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5duf RCSB], [https://www.ebi.ac.uk/pdbsum/5duf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5duf ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/ECHA6_MYCTU ECHA6_MYCTU] Could possibly oxidize fatty acids using specific components.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Phenotypic screens for bactericidal compounds against drug-resistant tuberculosis are beginning to yield novel inhibitors. However, reliable target identification remains challenging. Here, we show that tetrahydropyrazo[1,5-a]pyrimidine-3-carboxamide (THPP) selectively pulls down EchA6 in a stereospecific manner, instead of the previously assigned target Mycobacterium tuberculosis MmpL3. While homologous to mammalian enoyl-coenzyme A (CoA) hydratases, EchA6 is non-catalytic yet essential and binds long-chain acyl-CoAs. THPP inhibitors compete with CoA-binding, suppress mycolic acid synthesis, and are bactericidal in a mouse model of chronic tuberculosis infection. A point mutation, W133A, abrogated THPP-binding and increased both the in vitro minimum inhibitory concentration and the in vivo effective dose 99 in mice. Surprisingly, EchA6 interacts with selected enzymes of fatty acid synthase II (FAS-II) in bacterial two-hybrid assays, suggesting essentiality may be linked to feeding long-chain fatty acids to FAS-II. Finally, our data show that spontaneous resistance-conferring mutations can potentially obscure the actual target or alternative targets of small molecule inhibitors.

THPP target assignment reveals EchA6 as an essential fatty acid shuttle in mycobacteria.,Cox JA, Abrahams KA, Alemparte C, Ghidelli-Disse S, Rullas J, Angulo-Barturen I, Singh A, Gurcha SS, Nataraj V, Bethell S, Remuinan MJ, Encinas L, Jervis PJ, Cammack NC, Bhatt A, Kruse U, Bantscheff M, Futterer K, Barros D, Ballell L, Drewes G, Besra GS Nat Microbiol. 2016 Jan 18;1:15006. doi: 10.1038/nmicrobiol.2015.6. PMID:27571973<ref>PMID:27571973</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5duf" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Besra GS]]
[[Category: Cox JAG]]
[[Category: Futterer K]]