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| | <StructureSection load='5niz' size='340' side='right'caption='[[5niz]], [[Resolution|resolution]] 1.95Å' scene=''> | | <StructureSection load='5niz' size='340' side='right'caption='[[5niz]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5niz]] is a 1 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=5NIZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NIZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5niz]] 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=5NIZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NIZ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8YT:1-[3-[5-[(1~{R},2~{R})-2-methylcyclopropyl]furan-2-yl]propanoyl]piperidine-4-carboxamide'>8YT</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.95Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ethR, etaR, Rv3855 ([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=8YT:1-[3-[5-[(1~{R},2~{R})-2-methylcyclopropyl]furan-2-yl]propanoyl]piperidine-4-carboxamide'>8YT</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5niz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5niz OCA], [http://pdbe.org/5niz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5niz RCSB], [http://www.ebi.ac.uk/pdbsum/5niz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5niz ProSAT]</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=5niz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5niz OCA], [https://pdbe.org/5niz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5niz RCSB], [https://www.ebi.ac.uk/pdbsum/5niz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5niz ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ETHR_MYCTU ETHR_MYCTU]] Involved in the repression of the monooxygenase EthA which is responsible of the formation of the active metabolite of ethionamide (ETH).<ref>PMID:10869356</ref> <ref>PMID:10944230</ref> | + | [https://www.uniprot.org/uniprot/ETHR_MYCTU ETHR_MYCTU] Involved in the repression of the monooxygenase EthA which is responsible of the formation of the active metabolite of ethionamide (ETH).<ref>PMID:10869356</ref> <ref>PMID:10944230</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5niz" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5niz" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Tetracycline repressor protein 3D structures|Tetracycline repressor protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Baulard, A R]] | + | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Cole, J C]] | + | [[Category: Baulard AR]] |
| - | [[Category: Pohl, E]] | + | [[Category: Cole JC]] |
| - | [[Category: Tatum, N J]] | + | [[Category: Pohl E]] |
| - | [[Category: Dna binding protein]] | + | [[Category: Tatum NJ]] |
| - | [[Category: Protein ligand complex]]
| + | |
| - | [[Category: Tetr repressor]]
| + | |
| Structural highlights
Function
ETHR_MYCTU Involved in the repression of the monooxygenase EthA which is responsible of the formation of the active metabolite of ethionamide (ETH).[1] [2]
Publication Abstract from PubMed
The transcriptional repressor EthR from Mycobacterium tuberculosis, a member of the TetR family of prokaryotic homo-dimeric transcription factors, controls the expression of the mycobacterial mono-oxygenase EthA. EthA is responsible for the bio-activation of the second-line tuberculosis pro-drug ethionamide, and consequently EthR inhibitors boost drug efficacy. Here, we present a comprehensive in silico structure-based screening protocol that led to the identification of a number of novel scaffolds of EthR inhibitors in subsequent biophysical screening by thermal shift assay. Growth inhibition assays demonstrated that five of the twenty biophysical hits were capable of boosting ethionamide activity in vitro, with the best novel scaffold displaying an EC50 of 34 muM. In addition, the co-crystal structures of EthR with four new ligands at resolution ranging from 2.1 to 1.4 A confirm the binding and inactivation mode, and will enable future lead development.
New active leads for tuberculosis booster drugs by structure-based drug discovery.,Tatum NJ, Liebeschuetz JW, Cole JC, Frita R, Herledan A, Baulard AR, Willand N, Pohl E Org Biomol Chem. 2017 Nov 28. doi: 10.1039/c7ob00910k. PMID:29182187[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Baulard AR, Betts JC, Engohang-Ndong J, Quan S, McAdam RA, Brennan PJ, Locht C, Besra GS. Activation of the pro-drug ethionamide is regulated in mycobacteria. J Biol Chem. 2000 Sep 8;275(36):28326-31. PMID:10869356 doi:10.1074/jbc.M003744200
- ↑ DeBarber AE, Mdluli K, Bosman M, Bekker LG, Barry CE 3rd. Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9677-82. PMID:10944230
- ↑ Tatum NJ, Liebeschuetz JW, Cole JC, Frita R, Herledan A, Baulard AR, Willand N, Pohl E. New active leads for tuberculosis booster drugs by structure-based drug discovery. Org Biomol Chem. 2017 Nov 28. doi: 10.1039/c7ob00910k. PMID:29182187 doi:http://dx.doi.org/10.1039/c7ob00910k
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