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| | <StructureSection load='4m3g' size='340' side='right'caption='[[4m3g]], [[Resolution|resolution]] 2.30Å' scene=''> | | <StructureSection load='4m3g' size='340' side='right'caption='[[4m3g]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4m3g]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M3G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4M3G FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4m3g]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M3G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4M3G FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2G1:4-(2-METHYL-1,3-THIAZOL-4-YL)-N-(3,3,3-TRIFLUOROPROPYL)BENZENESULFONAMIDE'>2G1</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2G1:4-(2-METHYL-1,3-THIAZOL-4-YL)-N-(3,3,3-TRIFLUOROPROPYL)BENZENESULFONAMIDE'>2G1</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4m3b|4m3b]], [[4m3d|4m3d]], [[4m3e|4m3e]], [[4m3f|4m3f]]</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=4m3g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m3g OCA], [https://pdbe.org/4m3g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4m3g RCSB], [https://www.ebi.ac.uk/pdbsum/4m3g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4m3g ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">etaR, ethR, MT3970, Rv3855 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</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=4m3g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m3g OCA], [http://pdbe.org/4m3g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4m3g RCSB], [http://www.ebi.ac.uk/pdbsum/4m3g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4m3g 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 4m3g" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4m3g" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Tetracycline repressor protein 3D structures|Tetracycline repressor protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| Line 25: |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Myctu]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Baulard, A]] | + | [[Category: Baulard A]] |
| - | [[Category: Blondiaux, N]] | + | [[Category: Blondiaux N]] |
| - | [[Category: Brodin, P]] | + | [[Category: Brodin P]] |
| - | [[Category: Crauste, C]] | + | [[Category: Crauste C]] |
| - | [[Category: Deprez, B]] | + | [[Category: Deprez B]] |
| - | [[Category: Flipo, M]] | + | [[Category: Flipo M]] |
| - | [[Category: Leroux, F]] | + | [[Category: Leroux F]] |
| - | [[Category: Malaquin, S]] | + | [[Category: Malaquin S]] |
| - | [[Category: Piveteau, C]] | + | [[Category: Piveteau C]] |
| - | [[Category: Sperandio, O]] | + | [[Category: Sperandio O]] |
| - | [[Category: Villemagne, B]] | + | [[Category: Villemagne B]] |
| - | [[Category: Villeret, V]] | + | [[Category: Villeret V]] |
| - | [[Category: Villoutreix, B]] | + | [[Category: Villoutreix B]] |
| - | [[Category: Willand, N]] | + | [[Category: Willand N]] |
| - | [[Category: Wintjens, R]] | + | [[Category: Wintjens R]] |
| - | [[Category: Wohlkonig, A]] | + | [[Category: Wohlkonig A]] |
| - | [[Category: Helix-turn-helix dna binding protein]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Tetr-family]]
| + | |
| - | [[Category: Transcription repressor-inhibitor complex]]
| + | |
| - | [[Category: Transcriptional regulatory 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
Tuberculosis remains a major cause of mortality and morbidity, killing each year more than one million people. Although the combined use of first line antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol) is efficient to treat most patients, the rapid emergence of multidrug resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. Mycobacterial transcriptional repressor EthR is a key player in the control of second-line drugs bioactivation such as ethionamide and has been shown to impair the sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. As a way to identify new potent ligands of this protein, we have developed fragment-based approaches. In the current study, we combined surface plasmon resonance assay, X-ray crystallography, and ligand efficiency driven design for the rapid discovery and optimization of new chemotypes of EthR ligands starting from a fragment. The design, synthesis, and in vitro and ex vivo activities of these compounds will be discussed.
Ligand Efficiency Driven Design of New Inhibitors of Mycobacterium tuberculosis Transcriptional Repressor EthR Using Fragment Growing, Merging, and Linking Approaches.,Villemagne B, Flipo M, Blondiaux N, Crauste C, Malaquin S, Leroux F, Piveteau C, Villeret V, Brodin P, Villoutreix BO, Sperandio O, Soror SH, Wohlkonig A, Wintjens R, Deprez B, Baulard AR, Willand N J Med Chem. 2014 Jun 12;57(11):4876-88. doi: 10.1021/jm500422b. Epub 2014 May 28. PMID:24818704[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
- ↑ Villemagne B, Flipo M, Blondiaux N, Crauste C, Malaquin S, Leroux F, Piveteau C, Villeret V, Brodin P, Villoutreix BO, Sperandio O, Soror SH, Wohlkonig A, Wintjens R, Deprez B, Baulard AR, Willand N. Ligand Efficiency Driven Design of New Inhibitors of Mycobacterium tuberculosis Transcriptional Repressor EthR Using Fragment Growing, Merging, and Linking Approaches. J Med Chem. 2014 Jun 12;57(11):4876-88. doi: 10.1021/jm500422b. Epub 2014 May 28. PMID:24818704 doi:http://dx.doi.org/10.1021/jm500422b
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