5duc: Difference between revisions

Latest revision as of 22:00, 28 June 2023

Crystal structure of M. tuberculosis EchA6 bound to ligand GSK951A

Structural highlights

5duc is a 3 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.704Å
Ligands:	G51
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ECHA6_MYCTU Could possibly oxidize fatty acids using specific components.

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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. THPP target assignment reveals EchA6 as an essential fatty acid shuttle in mycobacteria. Nat Microbiol. 2016 Jan 18;1:15006. doi: 10.1038/nmicrobiol.2015.6. PMID:27571973 doi:https://dx.doi.org/10.1038/nmicrobiol.2015.6

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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. THPP target assignment reveals EchA6 as an essential fatty acid shuttle in mycobacteria. Nat Microbiol. 2016 Jan 18;1:15006. doi: 10.1038/nmicrobiol.2015.6. PMID:27571973 doi:https://dx.doi.org/10.1038/nmicrobiol.2015.6

[1]

@@ Line 3: / Line 3: @@
 <StructureSection load='5duc' size='340' side='right'caption='[[5duc]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5duc]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DUC OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5DUC FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5duc]] is a 3 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=5DUC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DUC FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G51:(5R,7S)-N-(1,3-BENZODIOXOL-5-YLMETHYL)-5-(4-ETHYLPHENYL)-7-(TRIFLUOROMETHYL)-4,5,6,7-TETRAHYDROPYRAZOLO[1,5-A]PYRIMIDINE-3-CARBOXAMIDE'>G51</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.704&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">echA6, Rv0905, MTCY31.33 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G51:(5R,7S)-N-(1,3-BENZODIOXOL-5-YLMETHYL)-5-(4-ETHYLPHENYL)-7-(TRIFLUOROMETHYL)-4,5,6,7-TETRAHYDROPYRAZOLO[1,5-A]PYRIMIDINE-3-CARBOXAMIDE'>G51</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Enoyl-CoA_hydratase Enoyl-CoA hydratase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.17 4.2.1.17] </span></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=5duc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5duc OCA], [https://pdbe.org/5duc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5duc RCSB], [https://www.ebi.ac.uk/pdbsum/5duc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5duc ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5duc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5duc OCA], [http://pdbe.org/5duc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5duc RCSB], [http://www.ebi.ac.uk/pdbsum/5duc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5duc ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/ECHA6_MYCTU ECHA6_MYCTU]] Could possibly oxidize fatty acids using specific components.
+[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 ==
@@ Line 24: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Enoyl-CoA hydratase]]
 [[Category: Large Structures]]
-[[Category: Besra, G S]]
+[[Category: Mycobacterium tuberculosis]]
-[[Category: Cox, J A.G]]
+[[Category: Besra GS]]
-[[Category: Futterer, K]]
+[[Category: Cox JAG]]
-[[Category: Enoyl-coa hydratase-like]]
+[[Category: Futterer K]]
-[[Category: Lipid binding protein]]
-[[Category: Lyase]]

5duc: Difference between revisions

Latest revision as of 22:00, 28 June 2023

Crystal structure of M. tuberculosis EchA6 bound to ligand GSK951A

Structural highlights

Function

Publication Abstract from PubMed

References

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